JP2018503434A - Pulsed electromagnetic therapy and ultrasound therapy for stimulating targeted heat shock proteins and promoting protein repair - Google Patents

Abstract

Stimulates heat shock protein activation in cells and tissues to take advantage of the therapeutic and restorative nature of increased heat shock protein activation or production and protein repair without damaging cells and tissues And systems and methods for promoting protein repair are presented. This achieves the necessary temperature increase to stimulate heat shock protein production or activation and promote protein repair while lowering the temperature fast enough so as not to damage or destroy the treated tissue, or Designated target area with a source of ultrasonic or electromagnetic radiation that is pulsed and applied or focused on one or more small areas to fully stress cells and tissues Is achieved by treating. [Selection] Figure 2

Description

  The present invention relates generally to the activation of heat shock proteins and the promotion of protein repair. More specifically, the present invention utilizes a pulsatile electromagnetic source or ultrasonic energy source to selectively stimulate activation and production of targeted heat shock proteins and promote protein repair. The present invention relates to a system and method.

  Heat shock proteins (HSPs) are a family of proteins that are produced by cells in response to exposure to stressful symptoms. Production of high levels of heat shock proteins can be caused by exposure to different types of environmental stress conditions such as infection, inflammation, exercise, exposure of cells to toxins, starvation, hypoxia, or water deficiency.

  Heat shock proteins are known to play a role in responding to a number of abnormal conditions in body tissues, including viral infections, inflammation, malignancy, oxidant exposure, cytotoxins, and hypoxia . Some heat shock proteins function as intracellular chaperones for other proteins, and members of the HSP family are those in simple protein monitoring in protein maintenance and even under stress-free conditions It is expressed or activated at low to moderate levels because of its essential role. These activities are part of the cell's own repair system and are referred to as the cell's stress response or heat shock response.

  Heat shock proteins are typically named according to their molecular weight. For example, Hsp60, Hsp70, and Hsp80 refer to a family of heat shock proteins that are approximately 60, 70, and 80 kilodaltons in size, respectively. They act in many different ways. For example, Hsp70 has a peptide binding domain and an ATPase domain that stabilizes the protein structure in an unfolded and competent state. Mitochondrial Hsp60s forms a ring-like structure that facilitates protein assembly into the natural state. Hsp90 plays a suppressor regulatory role by binding to cellular tyrosine kinases, transcription factors, and glucocorticoid receptors. Hsp27 suppresses protein aggregation.

  Hsp70 heat shock proteins are members of extracellular and membrane-bound heat shock proteins involved in antigen binding and presentation to the immune system. Hsp70 was found to inhibit the activity of the influenza A virus ribonucleoprotein and prevent viral replication. Tumor-derived heat shock proteins elicit specific protective immunity. Experimental and clinical observations have shown that heat shock proteins are involved in the regulation of autoimmune arthritis, type 1 diabetes mellitus, arteriosclerosis, multiple sclerosis, and other autoimmune responses.

  Thus, it is believed that it would be advantageous to be able to selectively induce a heat shock response to increase the number or activity of heat shock proteins in body tissues in response to infection or other abnormalities. However, this must be done in a controlled manner so as not to damage or destroy the body tissue or area being treated. The present invention fulfills these needs and provides other related advantages.

  The present invention relates to a method of stimulating the activation of heat shock proteins in tissue without damaging the target tissue. The method includes providing a source of pulsed ultrasonic or electromagnetic energy. The electromagnetic energy may include ultraviolet light, microwaves, radio frequency or laser light at a predetermined wavelength. The laser light may have a wavelength between 530 nm and 1300 nm, a duty cycle of less than 10%, and a pulse length of 500 milliseconds or less.

  Pulsed ultrasonic or electromagnetic radiant energy is applied to the target tissue to provide a thermal time course that stimulates the cells of the target tissue to activate the heat shock protein without damaging the target tissue. The This involves raising the temperature of the target tissue only by 1 ° C. or less over a few minutes, but temporarily at least 10 ° C.

  In one embodiment, multiple laser light spots are applied to the target tissue simultaneously. In another embodiment, the multiple ultrasound beams are focused on the target tissue.

  A device may be inserted into the body cavity to apply pulsed ultrasonic or electromagnetic radiant energy to the tissue. The device may include an endoscope.

  Pulsed ultrasonic or electromagnetic radiant energy can be applied to an external region of the body, the external region of the body being adjacent to the target tissue or having a blood supply near the surface of the external region of the body. For example, the body region may include an earlobe, and pulsed electromagnetic radiant energy is applied to blood flowing through the earlobe.

  Other features and advantages of the present invention will become apparent from the following more detailed description, taken in conjunction with the accompanying drawings, illustrating by way of example the principles of the invention.

  The accompanying drawings illustrate the invention.

FIG. 1 is a schematic diagram of a light generation unit for generating time-series pulses according to the present invention, the light generation unit having a light pipe extending therefrom. FIG. 2 is a cross-sectional view of a photostimulation delivery device for delivering electromagnetic energy to a target tissue according to the present invention. FIG. 3 is a schematic diagram illustrating a system used to generate a laser beam in accordance with the present invention. FIG. 4 is a schematic view of an optical element used to generate a geometric pattern of laser light according to the present invention. FIG. 5 is a schematic diagram illustrating an alternative embodiment of a system used to generate a laser beam for a target tissue according to the present invention. FIG. 6 is a schematic diagram illustrating yet another embodiment of a system used to generate a laser beam for treating tissue in accordance with the present invention. FIG. 7 is a cross-sectional schematic view of the end of an endoscope inserted into the nasal cavity and treating tissue in accordance with the present invention. FIG. 8 is a schematic, partial cross-sectional view of a bronchoscope that extends through the trachea to the bronchi of the lung and provides treatment there, according to the present invention. FIG. 9 is a schematic view of a colonoscope providing light stimulation to the intestinal or colonic region of the body according to the present invention. FIG. 10 is a schematic view of an endoscope inserted into the stomach and providing treatment thereto according to the present invention. FIG. 11 is a partial cross-sectional perspective view of a capsule endoscope used in accordance with the present invention. FIG. 12 is a schematic diagram of pulsed high intensity focused ultrasound for treating tissue in the body according to the present invention. FIG. 13 is a schematic diagram of a delivery treatment to a patient's bloodstream via an earlobe according to the present invention. FIG. 14 is a cross-sectional view of a treatment device that provides the stimulation of the present invention used to deliver light stimulation to blood via the earlobe according to the present invention.

  As shown in the accompanying drawings and as described more fully herein, the present invention stimulates heat shock protein activation or production and promotes protein repair without causing damage, The present invention relates to systems and methods for delivering energy sources, such as lasers, ultrasound, ultraviolet radio frequency, microwave radio frequency, etc. to cause a pulsed thermal time course in tissue.

  The inventors of the present invention have shown that beneficial effects on eye diseases have been achieved by applying electromagnetic radiation to retinal tissue in the form of various wavelengths of laser light in a manner that does not destroy or damage retinal tissue. discovered. It is believed that this may be due, at least in part, to the stimulation and activation of heat shock proteins and the promotion of protein repair in retinal tissue. No. 14 / 607,959, filed Jan. 28, 2015, No. 13 / 798,523, filed Mar. 13, 2013, and filed on May 25, 2012. 13 / 481,124, the contents of which are hereby incorporated by reference in their entirety.

  The inventor is therapeutic but sublethal to retinal tissue cells and thus provides a prophylactic and protective treatment of ocular retinal tissue for photocoagulation in retinal tissue. It has been found that a laser beam can be generated that avoids damage. The inventor produces subthreshold and sublethal micropulse laser beams with a wavelength greater than 532 nm and a duty cycle of less than 10% with a predetermined intensity or power and a predetermined pulse length or exposure time. Has been found to result in desirable retinal light stimulation without visible burn areas or tissue destruction. More specifically, between 550 nm and 1300 nm, and in particularly preferred embodiments, a wavelength of 810 nm, a duty cycle of approximately 5% or less and a predetermined intensity or power (100-590 watts per square centimeter in the retina or retina A laser beam having a predetermined pulse length or exposure time (such as 500 milliseconds or less) and a retinal pigment that has been exposed to laser irradiation. All areas of the epithelium are protected and provide sub-lethal "sub-true threshold" retinal photocoagulation that can be therapeutically contributed. In other words, the inventor must destroy, burn or otherwise retinal tissue by raising it to a level at least to a therapeutic level, but below the lethal level of the cell or tissue. It has been found that the benefits of the halo effect of the prior art method are again brought about without damage. This is referred to herein as subthreshold diode micropulse laser therapy (SDM).

  SDM does not cause laser-induced retinal damage (photocoagulation) and has no known adverse treatment effects (diabetic macular edema (DME), proliferative diabetic retinopathy (PDR), retinal vein) It is an effective treatment in many retinal disorders (including macular edema caused by branch blockage (BRVO), central serous chorioretinopathy (CSR), reversal of drug resistance), atrophic age-related macular degeneration, Stargardt It has been reported to be a prophylactic treatment for progressive degenerative retinopathy such as disease, cone dystrophy, and retinitis pigmentosa. The safety of SDM is such that it can be used across the fovea in an eye with 20/20 vision to reduce the risk of vision loss due to DME associated with the early fovea. is there.

  The mechanism by which SDM may act is the production or activation of heat shock proteins (HSPs). Despite the almost unlimited variety of cellular abnormalities, all types of cells share a common and highly conserved repair mechanism: heat shock protein (HSP). HSP is triggered almost immediately in seconds to minutes by stress or damage to almost any type of cell. In the absence of lethal cell damage, HSP is extremely effective in restoring and restoring live cells to a more normal functional state. HSPs are temporary and generally peak in a few hours and last for a few days, but their effects can last long. HSP reduces inflammation, a common factor in many disorders.

  Laser therapy can induce HSP generation or activation and alter cytokine expression. The more sudden and severe the non-fatal cell stress (such as laser irradiation), the faster and stronger the HSP activation. Thus, a burst of repetition at the very rapid rate of change (each with a 100 μs micropulse up to 7 ° C. or 70,000 ° C./sec) caused by each SDM exposure The low-temperature heat spikes of Stim stimulate HSP activation, especially compared to non-fatal exposure to sub-threshold treatment with a continuous wave laser, which can only duplicate a low average tissue temperature rise It is particularly effective.

  Laser wavelengths below 550 nm result in increasing photochemical effects of cytotoxicity. At 810 nm, SDM provides photothermal rather than photochemical cellular stress. Thus, SDM can affect tissue without damaging the tissue. Thus, the clinical utility of SDM is brought about by sub-morbid photothermal cellular HSP activation. In dysfunctional cells, HSP stimulation with SDM results in normalization of cytokine expression and ultimately improved structure and function. The therapeutic effect of this “low intensity” laser / tissue interaction is then amplified by the application of “high density” laser to densely / consolidate large tissue areas, including all areas of the disease state Thereby mobilizing all dysfunctional cells to the targeted tissue region, thereby maximizing the treatment effect. These principles define the treatment strategies for SDM described herein.

  Because normally functioning cells do not require repair, HSP stimulation in normal cells tends to have no significant clinical effect. The “patho-selectivity” of near-infrared laser effects such as SDM that affect pathological cells but not normal cells for various cell types is consistent with clinical observations of SDM. Yes. SDM has been reported to have a unique and clinically broad therapeutic range of retinal laser methods, consistent with the predictions of the American National Standards Institute “Maximum Permissible Exposure”. SDM can cause direct photothermal effects such as unfolding and disaggregation of entropic proteins, but appears to be optimized for clinically safe and effective stimulation of HSP-mediated repair appear.

  As noted above, the SDM stimulation of HSP is non-specific with respect to the disease process, while the consequences of HSP-mediated repair are specific to the dysfunctional state by nature. HSPs tend to repair anything that is wrong. Thus, the effectiveness of SDM observed in retinal symptoms is widely different from BRVO, DME, PDR, CSR, aging and hereditary retinopathy, and drug-resistant NAMD. Conceptually, this capability can be thought of as a type of “Reset to Default” mode of SDM action. For a wide range of retinal disorders where cell function is critical, SDM normalizes cell function by causing a “reset” (to “factory settings”) by HSP-mediated cell repair.

  The inventors have discovered that SDM treatment of patients with age-related macular degeneration (AMD) can also slow or stop the progression of AMD. Most of the patients showed significant improvement in dynamic functional logMAR twilight and tactile contrast after SDM treatment. SDM is thought to act by targeting and protecting the retinal pigment epithelium (RPE) and “normalizing” (closer to normal) its function.

  SDM has been shown to be able to stop or reverse the onset of the disease state of diabetic retinopathy without treatment-related damage or side effects despite the persistence of systemic diabetes. Based on this, SDM is more like normal cell function and cytokine expression in RPE cells affected by diabetes, similar to pressing the “reset” button on the electronic device to restore factory settings. It is assumed to work by inducing back to back. Based on the above information and studies, SDM treatment can directly affect cytokine expression by heat shock protein (HSP) activation in target tissues.

  Since heat shock proteins play a role in responding to a number of abnormal conditions in body tissues other than ocular tissues, similar systems and methodologies may be advantageously used to treat such abnormal conditions, infections, etc. It is considered possible. As such, the present invention provides ultrasound for treating abnormal conditions, including inflammation, autoimmune symptoms, and cancer, which can be utilized by focused electromagnetic waves / sonic waves in addition to endoscopic or surface probe fiber optics. Relates to controlled application of electromagnetic or electromagnetic radiation. For example, cancer on the surface of the prostate with the greatest threat of metastasis can be accessed by fiber optics in a rectoscope. Colon tumors are possible with fiber optic systems, such as those used in colonoscopy.

  As shown above, sub-threshold diode micropulse laser (SDM) light stimulation is effective in stimulating the direct repair of slightly misfolded proteins in ocular tissue. In addition to HSP activation, this can occur in another way because the temperature spikes caused by micropulses in the form of a thermal time course allow the diffusion of water within the protein, thereby This is because the peptide-peptide hydrogen bond can be broken to prevent the protein from returning to its natural state. The diffusion of water into the protein results in an approximately 1000-fold increase in the number of restraining hydrogen bonds. Thus, it is believed that this process can be applied to other diseases as well.

  The light stimulus according to the present invention can be effectively delivered to an internal surface region or tissue of the body using an endoscope, such as a bronchoscope, a rectoscope, a colonoscope and the like. Each of these consists essentially of a flexible tube, which itself includes one or more inner tubes. Typically, one of the inner tubes is a light pipe or multiple that illuminates the area of interest and directs the light down the scope so that the physician can see what is at the illuminated end. Includes mode fiber optics. Another inner tube may consist of a wire that carries current to allow the physician to cauterize the irradiated tissue. Yet another inner tube may consist of a biopsy tool that allows the physician to cut and hold any of the irradiated tissue.

  In the present invention, one of these inner tubes is used as an electromagnetic radiation pipe, such as a multimode optical fiber, to which SDM or other electromagnetic radiation pulses are delivered and fed to the mirror at the end held by the physician. The Referring now to FIG. 1, a light generation unit 10, such as a laser having a desired wavelength and / or frequency, is inserted into the body and lighted to the distal end of a mirror 14, illustrated in FIG. Used to generate electromagnetic radiation, such as a laser beam, in a controlled, pulsed manner delivered through a tube or light pipe 12, the laser light or other radiation 16 being treated target tissue 18 delivered.

  Referring now to FIG. 3, a schematic diagram of a system for generating electromagnetic energy radiation, such as laser light, including SDM is shown. The system generally referred to by reference numeral 20 includes a laser console 22, such as, for example, a 810 nm near infrared micropulse diode laser in the preferred embodiment. The laser produces a laser beam that is passed through an optical lens or mask, or a plurality of optical lenses or masks 24 as required. The laser projector optical element 24 passes the formed beam through a delivery device 26, such as an endoscope, to project a laser beam onto the target tissue of the patient. It is understood that the box labeled 26 can represent both a laser beam projector or delivery device and a viewing system / camera such as an endoscope, or includes two different components in use. The viewing system / camera 26 may also include the necessary computerized hardware, data input and control, etc. for operating the laser 22, optical element 24, and / or projection / viewing component 26. Provide feedback to 28.

  Referring now to FIG. 4, in one embodiment, the laser beam 30 can be passed through a collimator lens 32 and then through a mask 34. In a particularly preferred embodiment, the mask 34 includes a diffraction grating. The mask / diffraction grating 34 provides a geometric object, or more typically a geometric pattern of multiple laser spots generated simultaneously, or other geometric objects. This is represented by a plurality of laser beams labeled 36. Alternatively, multiple laser spots can be generated by multiple fiber light guides. Any method of generating a laser spot allows a large number of laser spots to be generated simultaneously over a very wide therapeutic field. In fact, a large number of laser spots, perhaps hundreds, thousands or more, can be generated simultaneously to cover a given area of the target tissue, or even the entire target tissue. To avoid certain drawbacks and treatment risks known to be associated with the application of large laser spots, it may be desirable to apply a wide series of simultaneously applied small isolated laser spots.

  Quantities that allow the simultaneous application of a large number of laser spots for very large target areas, for example using diffraction gratings, using optical features that have a shape size equivalent to the wavelength of the laser utilized It is possible to take advantage of mechanical effects. All of the individual spots generated by such a diffraction grating are optically similar to the incident beam with minimal power variation for each spot. As a result, multiple laser spots with sufficient irradiance provide harmless and effective therapeutic applications simultaneously over a large target area. The present invention also contemplates the use of other geometric objects and patterns provided by diffractive optical elements.

  The laser light that passes through the mask 34 is diffracted, resulting in a periodic pattern that is spaced from the mask 34, as shown by the laser beam labeled 36 in FIG. The single laser beam 30 was therefore shaped into hundreds or thousands of individual laser beams 36 to create a desired spot pattern or other geometric object. These laser beams 36 can be passed through additional lenses, collimators 38 and 40, etc. to transmit the laser beam and form the desired pattern. Such additional lenses, such as collimators 38 and 40, can further convert and redirect the laser beam 36 as needed.

  By controlling the shape, spacing, and pattern of the optical mask 34, an arbitrary pattern can be constructed. Patterns and exposure spots can be arbitrarily created and modified as desired according to application requirements by optical engineering experts. Photolithographic techniques, particularly those developed in the field of semiconductor manufacturing, can be used to create simultaneous geometric spot patterns or other objects.

  FIG. 5 schematically illustrates a system for coupling multiple light sources to an optical subassembly that generates the pattern described above. Specifically, this system 20 'is similar to the system 20 described in FIG. 3 above. The main difference between the alternative system 20 ′ and the previously described system 20 is that it includes multiple laser consoles, each of which outputs are fed to a fiber coupler 42. The fiber coupler produces a single output that is passed to the laser projector optics 24 as described in the previous system. The coupling of multiple laser consoles 22 to a single optical fiber is accomplished using a fiber coupler 42 as is known in the art. Other known mechanisms for combining multiple light sources are also available and may be used to replace the fiber couplers described herein.

  In this system 20 ′, the plurality of light sources 22 follow a path similar to that described in the previous system 20, ie collimated, diffracted, recollimated, and oriented into the projector device and / or tissue. The In this alternative system 20 ', the diffractive element must function differently than previously described, depending on the wavelength of light passing therethrough, which results in slight variations in the pattern. Connected. The change is linear with the wavelength of the light source being diffracted. In general, the difference in diffraction angles is small enough that different overlapping patterns can be oriented along the same optical path towards the tissue through the projector device 26 for treatment.

  Since the resulting pattern varies slightly for each wavelength, the successive offsets to achieve full coverage are different for each wavelength. Successive offsets can be achieved in two modes. In the first mode, all wavelengths of light are applied simultaneously without the same coverage. An offset steering pattern is used to achieve full coverage for one of the wavelengths. Thus, the selected wavelength of light achieves full coverage of the tissue, while other wavelengths of application achieve either incomplete coverage or overlapping coverage of the tissue. The second mode applies each light source of varying wavelength sequentially with an appropriate steering pattern to achieve full tissue coverage for that particular wavelength. This mode eliminates the possibility of simultaneous treatment using multiple wavelengths, but allows optical approaches to achieve the same coverage for each wavelength. This avoids incomplete and overlapping coverage for any of the optical wavelengths.

  These modes may also be combined and matched. For example, two wavelengths may be applied simultaneously so that one wavelength achieves full coverage and another wavelength achieves incomplete or overlapping coverage, after which the third wavelength is It can be applied continuously to achieve full coverage.

  FIG. 6 schematically illustrates yet another alternative embodiment of the system 20 ″ of the present invention. This system 20 '' is constructed in substantially the same way as the system 20 depicted in FIG. The main difference is that it includes subassembly channels that generate multiple patterns tailored to specific wavelengths of the light source. A plurality of laser consoles 22 are arranged in parallel, each one directly connected to its own laser projector optical element 24. The laser projector optics of each channel 44a, 44b, 44c includes a collimator 32, a mask or diffraction grating 34, and recollimators 38, 40, as described above in connection with FIG. The entire set of elements is tuned to a specific wavelength generated by the corresponding laser console 22. The output from each set of optical elements 24 is then directed to a beam splitter 46 for combination with other wavelengths. It is known to those skilled in the art that the reversely used beam splitter can be used to combine multiple rays into a single output.

  The combined channel output from the final beam splitter 46 c is then directed through the projector device 26.

  In this system 20 '', the optical elements for each channel are adjusted to produce an exact specified pattern for the wavelength of that channel. As a result, once all channels are combined and properly aligned, a single steering pattern can be used to achieve full coverage of the tissue for all wavelengths.

  System 20 '' may use as many channels 44a, 44b, 44c, etc. and beam splitters 46a, 46b, 46c, etc. as the wavelength of light being used in the procedure.

  Different symmetries can be exploited in the implementation of the system 20 "to reduce the number of alignment constraints. For example, the proposed grid pattern is periodic in two dimensions and is manipulated in two dimensions to achieve full coverage. As a result, if the pattern for each channel is identical to the specified pattern, the actual pattern of each channel need not be aligned with the same steering pattern to achieve full coverage for all wavelengths. right. Each channel only needs to be optically aligned to achieve an efficient combination.

  In the system 20 ", each channel starts with a light source 22, which can be from an optical fiber, such as in other embodiments of the subassembly that generates the pattern. This light source 22 is oriented to the optical assembly 24 for collimation, diffraction, recollimation, and orientation to a beam splitter that combines the channel with the main output.

  It will be appreciated that the system for generating laser light illustrated in FIGS. 3-6 is typical. Other devices and systems can be utilized to generate a source of SDM laser light that can be operatively passed through a projector device, typically in the form of an endoscope having a light pipe or the like. Other forms of electromagnetic radiation may be generated and used at predetermined wavelengths, including ultraviolet, microwave, other radio frequency waves, and laser light. In addition, ultrasound is also generated to provide a thermal time course temperature spike in the target tissue sufficient to activate or generate heat shock proteins in the target tissue cells without damaging the target tissue itself, May be used. To that end, typically a pulsed source of ultrasonic or electromagnetic radiant energy is provided, and the temperature of the target tissue is kept at 1 ° C. or less for extended periods of time, such as over 2 minutes over a few minutes. Yes, it is applied to the target tissue in a way that temporarily raises at least 10 ° C.

  For deep tissue that is not near the internal opening, the light pipe is not an effective means of delivering pulsed energy. In that case, pulsed low frequency electromagnetic energy or preferably pulsed ultrasound may be used to cause a series of temperature spikes in the target tissue.

  Thus, in accordance with the present invention, a source of pulsed ultrasonic or electromagnetic radiation is applied to the target tissue to stimulate HSP generation or activation and promote protein repair in living animal tissue. In general, the electromagnetic radiation can be ultraviolet, microwave, other radio frequency waves, laser light, such as at a predetermined wavelength. On the other hand, when electromagnetic energy is used for a deep tissue target away from the natural opening, the absorption length limits the wavelength to the wavelength of a microwave or radio frequency wave, depending on the depth of the target tissue. However, as will be explained later, ultrasound is preferred over long wavelength electromagnetic radiation for deep tissue targets remote from the natural opening.

  Ultrasound or electromagnetic radiation causes a thermal time course in the tissue and pulses to stimulate HSP generation or activation and promote protein repair without causing damage to the cells and tissues being treated. To be shaped. The area and / or volume of the treated tissue is also controlled so that the temperature spike is on the order of a few, for example around 10 ° C., while maintaining the long-term temperature rise below the 1 ° C limit set by the FDA, Be minimized. It has been found that if the tissue area or volume to be treated is too large, the elevated tissue temperature cannot be diffused fast enough to meet FDA requirements. However, in addition to limiting the area and / or volume of the treated tissue, by creating a pulsed energy source, the surplus heat generated by the treated cells and tissue can be released within acceptable limits. While enabling, the object of the present invention to stimulate HSP activation or production is achieved by heating or otherwise stressing cells and tissues.

  It is believed that the stimulation of HSP generation according to the present invention can be effectively utilized in treating a wide range of tissue abnormalities, diseases and even infections. For example, the cold-causing virus primarily affects small ports of the respiratory epithelium in the nasal passages and nasopharynx. Like the retina, the respiratory epithelium is a thin and transparent tissue. Referring to FIG. 7, a cross-sectional view of a human head 48 is shown with an endoscope 14 inserted into the nasal cavity 50 and energy 16 such as laser light oriented at the tissue 18 to be treated in the nasal cavity 50. Has been. The tissue 18 to be treated can be in the nasal cavity 50, including the nasal passage and nasopharynx.

  The wavelength can be adjusted to the infrared (IR) absorption peak of water to ensure the absorption of the laser energy, or other energy source, or an adjuvant dye functions as a photosensitizer Can be used to In such cases, the treatment can then be taken by drinking or applying the adjuvant locally, waiting a few minutes for the adjuvant to penetrate the surface tissue, and then endoscopy as shown in FIG. 14 consists of administering laser light or other energy source 16 to the target tissue 18 for several seconds via an optical fiber in 14. To provide comfort to the patient, the endoscope 14 can be inserted after application of a local anesthetic. If necessary, the above procedure can be repeated periodically for about a day.

  As discussed above, treatment will stimulate heat shock protein activation or production and promote protein repair without damaging the cells and tissues being treated. As discussed above, certain heat shock proteins have been found to play an important role in the health of targeted cells and tissues in addition to immune responses. The energy source can be monochromatic laser light, such as laser light at a wavelength of 810 nm, and can be administered in a manner similar to that described in the above referenced patent application, but as shown in FIG. It can also be administered by an endoscope or the like. Adjuvant dyes will be selected to increase laser light absorption. This includes particularly preferred methods and embodiments for practicing the invention, but it will be appreciated that other types of energy and delivery means may be used to accomplish the same purpose in accordance with the invention.

  Referring now to FIG. 8, a similar situation exists for influenza viruses, where the primary target is the epithelium of the upper respiratory tree in the segment having a diameter greater than about 3.3 mm, ie, the upper respiratory tree. The upper six generations. A viscous thin layer separates the targeted epithelial cells from the airway lumen, in which interaction of antigen and antibody occurs resulting in viral inactivation.

  With continued reference to FIG. 8, the flexible light tube 12 of the bronchoscope 14 is inserted from the individual's mouth 52 through the throat and trachea 54 into the bronchi 56 of the respiratory tree. Here, laser light or other energy source 16 is applied to the tissue in this region of the top segment to treat the tissue and region in the same manner as described above with respect to FIG. Is done. The wavelength of the laser or other energy, along with its attendant benefits, matches the IR absorption peak of water present in the mucus to heat the tissue and stimulate HSP activation or production and promote protein repair It is devised to be selected.

  Referring now to FIG. 9, as illustrated, the colonoscope 14 is used to deliver the selected laser light or other energy source 16 to the area and tissue to be treated to the anus and rectum 58. The flexible light tube 12 may be inserted into the navel and into either the large intestine 60 or small intestine 62. This can be used to support other gastrointestinal problems besides treating colon cancer.

  Typically, the above procedure may be performed similar to colonoscopy, where all stool is removed from the intestine, the patient lies sideways, and the doctor The light tube portion 12 is inserted into the rectum and moved to the area of the colon, large intestine 60 or small intestine 64 in the area to be treated. The physician can see the path of the inserted flexible member 12 through the monitor and look at the tissue at the distal end of the colonoscope 14 in the intestine to see the area to be treated. I was able to. Using one of the other optical fibers or light tubes, the mirror tip 64 is directed to the tissue to be treated, and the source of laser light or other radiation 16 activates or produces HSP in the tissue 18. For stimulation, it is delivered through one of the light tubes of the colonoscope 14 to treat the area of tissue to be treated, as described above.

  Referring now to FIG. 10, another example in which the present invention can be advantageously used is the “Lieky gut” syndrome, which is a gastrointestinal (GI) tract symptom manifested by inflammation and other metabolic dysfunctions. It is called. Since the GI tract is vulnerable to metabolic dysfunction similar to the retina, it is expected to respond well to the treatment of the present invention. This is done by a sub-threshold, diode micropulse laser (SDM) therapy, as discussed above, or other energy sources and means as discussed herein and known in the art. obtain.

  With continued reference to FIG. 10, a flexible light tube 12, such as an endoscope, is inserted from the patient's mouth 52 through the throat and tracheal region 54 into the respiratory tree stomach 66, where the tip or The end 64 is oriented toward the tissue 18 to be treated and the laser light or other energy source 16 is oriented at the tissue 18. It will be appreciated by those skilled in the art that a colonoscope can also be used and inserted through the rectum 58 into the stomach 66 or any tissue between the stomach and the rectum.

  If necessary, the chromophore dye can be delivered orally to the GI tissue to allow absorption of radiation. For example, if unfocused 810 nm radiation from a laser diode or LED is used, the dye has an absorption peak at or near 810 nm. Alternatively, the wavelength of the energy source can be adjusted to a slightly longer wavelength at the water absorption peak so that no external application of the chromophore is required.

  It is contemplated by the present invention that a capsule endoscope 68, such as that shown in FIG. 11, can be used to provide a radiation and energy source in accordance with the present invention. Such capsule endoscopes are relatively small in size, such as approximately 1 inch in length, so as to be swallowed by the patient. Once the capsule or pill 68 is swallowed, enters the stomach and passes through the GI tract, at an appropriate location, the capsule or pill 68 activates an energy source 72 such as a laser diode and associated circuitry. Power and signals can be received, such as through 70, and a suitable lens 74 focuses the laser light or radiation generated through the radiation transparent cover 76 onto the tissue to be treated. The position of the capsule endoscope 68 can be determined by various means such as external diagnostic imaging, signal tracking, or by a small camera with illumination, where a physician views an image of the GI tract through which the pill or capsule 68 passes. Understood. The capsule or pill 68 can be supplied with its own power source by a battery, or it can be externally powered via an antenna, so that a laser diode is used to treat the tissue and area to be treated. A source that generates 72 or other energy creates the desired wavelength and pulsed energy source.

  As in retinal procedures in previous applications, the radiation is pulsed to take advantage of micropulse temperature spikes and associated safety, and the power is adjusted so that the procedure is completely harmless to the tissue. obtain. This adjusts the peak power, pulse time, and repetition rate to give a spike temperature increase of approximately 10 ° C while maintaining the long-term temperature increase below the 1 ° C limit set by the FDA. May be included. If a delivery pill form 68 is used, the device may be powered, such as by a small rechargeable battery or wireless inductive excitation. Heated or stressed tissue stimulates HSP activation or production, promotes protein repair, and is accompanied by its benefits.

  From the previous example, the technique of the present invention is limited to the treatment of symptoms near or on the body surface that can be readily utilized by fiber optics or other light delivery means. The reason that the application of SDM to activate HSP activity is limited to areas near the body surface or optically accessible is that the absorption length of IR or visible light in the body is very short. However, it is a condition deep within the tissue or body that benefits from the present invention. Accordingly, the present invention contemplates the use of ultrasound and / or radio frequency (RF) and even shorter wavelength electromagnetic (EM) radiation, which has a relatively long absorption length in body tissue. As described more fully below, the use of pulsed ultrasound is preferred over RF electromagnetic radiation to activate therapeutic HSP activity in abnormal tissues that do not have access to surface SDM or the like. Pulsed ultrasound sources can also be used abnormally at or near the surface.

  Referring now to FIG. 12, by using ultrasound, specific areas deep within the body can be specifically targeted by using one or more beams, each focused on a target site. Thereafter, pulsed heating is mostly applied only to the targeted area, where the beam is focused and overlapped.

  As illustrated in FIG. 12, an ultrasonic transducer 78 or the like generates a plurality of ultrasonic beams that are coupled to the skin via an acoustic impedance matching gel and in front of the focus of the beam 80. Through 82 and undamaged tissue, it penetrates to the target organ 84, such as the illustrated liver, and specifically to the target tissue 86 to be treated to which the ultrasound beam 80 is focused. As mentioned above, pulsed heating is then only applied to the targeted focusing region 86 where the focused beam 80 overlaps. The tissue in front of and behind the focusing region 86 is not appreciably heated or affected.

  Examples of parameters that give an Arrhenius integral of desirable HSP activation greater than 1 and an Arrhenius integral of damage less than 1 are 5.8-17 watts total ultrasonic power, 10 pulses within a total pulse train time of 50 seconds With a pulse duration of 0.5 seconds and a pulse interval of 5 seconds. The target treatment volume is approximately 1 mm on the side. By applying ultrasound in multiple simultaneously applied adjacent but separately spaced rows, a larger treatment volume is similar to a laser diffracted optical system (described above) It may be treatable by an ultrasound system. As mentioned above, multiple focused ultrasound beams converge on a very small treatment target in the body, which allows for minimal heating other than overlapping beams at the target. This region is heated and a temporary high temperature spike stimulates HSP activation and promotes protein repair. However, considering the relatively small area being treated at a given time in addition to the pulsed aspect of the present invention, the treatment follows FDA / FCC requirements for long term (minute) average temperature rise <1K. An important difference of the present invention from the existing hyperthermia treatment of pain and muscle tone is that the existing technology does not have a high T spike and efficiently activates HSP to provide healing at the cellular level. And need to promote protein repair.

  As long as therapeutic HSP activation and promotion of protein repair are involved, the pulse train mode of energy delivery has different advantages than the single pulse or stepwise mode of energy delivery. There are two considerations for this advantage:

  For one, the great advantage for HSP activation and protein repair in the SDM energy delivery mode results from the generation of a spike temperature of approximately 10 ° C. This large temperature rise has a major impact on the Arrhenius integration that quantitatively describes the number of activated HSPs and the rate of water diffusion into the protein that promotes protein repair. This is because temperature falls into an exponential with a large amplification effect.

  It is important that the temperature rise does not stay high (10+ degrees) for a long time because it violates the FDA and FCC requirements, where the average temperature rise must be less than 1 ° C over a period of minutes Because.

  The SDM mode of energy delivery uniquely satisfies both these previous considerations by the judicious choice of power, pulse time, pulse interval, and volume of target site to be treated. Because the temperature must drop from its high value of the order of approximately 10 ° C fairly quickly so that the long-term average temperature rise does not exceed the long-term 1 ° C FDA / FCC limit, (Enters).

For a region of length dimension L, the time it takes for the peak temperature to e-fold in the tissue is approximately L ² / 16D, where D = 0.143 cm ² / sec is Typical thermal diffusion coefficient. For example, when L = 1 mm, the fall time is approximately 0.4 seconds. Thus, for a 1 mm side area, a sequence of 10 pulses, each with a duration of 0.5 seconds, with a 5 second pulse interval, will exceed an average long-term temperature rise of 1 ° C. The desired instantaneous high temperature rise can be achieved. This is further demonstrated below.

  The reason for the limited capacity to heat is that RF electromagnetic radiation is not a good choice for SDM type treatments in deeper areas of the body. Long epidermal depth (penetration distance) and ohmic heating along the entire epidermal depth results in a large amount of heating, which thermal inertia achieves high spike temperatures that activate HSP and promote protein repair , And does not allow a rapid temperature drop to meet the long-term FDA and FCC limits for average temperature rise.

  Ultrasound has already been used to therapeutically heat areas of the body to relieve pain and muscle tone. However, heating does not follow an SDM type protocol and does not have a temperature spike that is responsible for HSP excitation.

  Now consider a group of focused ultrasound beams that are oriented at a deep target site within the body. To simplify the mathematics, assume that the beam is replaced with a single source having a spherical shape focused at the center of the sphere. The absorption length of ultrasound can be quite long. Table 1 below shows typical absorption coefficients for ultrasound at 1 MHz. The absorption coefficient is almost proportional to the frequency.

Assuming that the geometric deformation of the incident due to focusing is dominant over the deformation due to attenuation, the intensity of the ultrasound incident at a distance r from the focal point is calculated approximately as follows:
I (r) = P / (4πr ² ) [1]
In the formula, P represents the total ultrasonic power.
temperature rise at the end of a short pulse duration t _p of r is less than or equal to,
dT (t _p ) = Pαt _p / (4πC _v r ² ) [2]
In the formula, α is an absorption coefficient, and _Cv is a specific heat capacity. Until in doing so, to the thermal diffusion length in t _p until r until it becomes comparable to the r is achieved, or reaches the diffraction limit of the focused beam, this is true. For shorter r, the temperature rise is essentially independent of r. As an example, assume that the diffraction limit has been reached with a radial distance shorter than that determined by thermal diffusion. here,
r _dif = (4Dt _p ) ^1/2 [3]
, And the formula, D is the thermal diffusion coefficient with respect to _{r <r dif,} the temperature rise at _{t p} are the following:
When dT (r _dif , t _p ) = 3Pα / (8πC _v D) r <r _dif [4]
Thus, at the end of the pulse, the temperature rise can be recorded:
dt _p (r) = {Pαt _p / (4πC _v } [(6 / r _dif ² ) U {r _dif −r) + (1 / r ² ) U] (r−r _dif )] [5]
Thermal diffusion equation for the Green's function G (r, t) = ( 4ΩDt) -3/2 exp [-r 2 / (4Dt)] [6]
Is applied to this initial temperature distribution, the temperature dT (t) at the focal point r = 0 at time t was found to be:
dT (t) = [dT _o / {(1/2) + (π ^1/2 / 6)}] [(1/2) (t _p / t) ^3/2 + (π ^1/2 / 6) (T _p / t)] [7]
And dT _o = 3Pα / (8πC _v D) [8]

  A good approximation to equation [7] is provided by the following, as can be seen in graph 1 below:

The Arrhenius integral for a train of N pulses can now be evaluated using the temperature rise given by equation [9]. In this formula:

Where dT (t−nt _I ) is the equation of equation [9] where t replaces t−nt _I and t _I indicates the pulse interval.

Arrhenius integration can be approximated by dividing the integration interval into parts where temperature spikes occur and where there are no temperature spikes. The summation over the temperature spike contribution can be simplified by applying the Laplace's end point formula to the integral over the temperature spike. Furthermore, the integral for the part without spikes, the temperature rise without spikes reaches the asymptotic value very quickly, so that a good approximation can be obtained by replacing the changing time rise with that asymptotic value. It can be simplified by noting that. When these approximations are obtained, equation [10] becomes:
^{_{Ω = AN [{t p (}} 2k B T o 2 /} (3EdT o) exp [- (E / k B) 1 / (T o + dT o + dT N (Nt I))]
+ Exp [− (E / k _B ) 1 / (T _o + dT _N (Nt _I ))]] [12]
Where:

(2.5 in equation [13] arises from the sum of (N−n) ^−3/2 to n and is the magnitude of the harmonic number (N, ^3/2 ) for a typical N of interest. )

It is interesting to compare this expression with that for SDM applied to the retina. The first term is very similar to the condition from the spike contribution in the case of the retina, except that the effective spike spacing is reduced by a factor of 3 for this 3D focused beam. The second is that it contains much less dT _N (Nt _I ) than in the retina. Here, the background temperature rise was comparable in magnitude to the spike temperature rise. However, in the case of a focused beam here, the background temperature rise is much smaller depending on the ratio (t _p / t _I ) ^3/2 . Since the background temperature rise, similar to that in the case of continuous ultrasonic heating, is not significant compared to the spike contribution, this is an indication of the spike contribution to HSP activation or generation and the promotion of protein repair. Emphasizes the importance. At the end of the pulse train, even this low background temperature rise stops rapidly due to thermal diffusion.

Graph 2 below shows Arrhenius for damage and for activation or generation of HSP as a function of dT _o for pulse duration t _p = 0.5 seconds, pulse interval t _I = 10 seconds, and total number of pulses N = 10. Indicates the logarithm of the integral.

Graph 2. Pulse duration _t p = 0.5 s, pulse interval _t I = 10 seconds, and the total number of ultrasonic pulses N = 10, corresponding to the temperature increase of the absolute temperature of the single pulse dT _o, and against damage Logarithm of Arrhenius integral [Equation 12] for HSP activation. Graph 2a shows the logarithm of the damage integral at the Arrhenius constant A = 8.71 × 10 ³³ sec ⁻¹ and E = 3.55 × 10 ⁻¹² ergs. Graph 2b shows the logarithm of HSP activation integral with Arrhenius constant A = 1.24 × 10 ²⁷ sec ⁻¹ and E = 2.66 × 10 ⁻¹² ergs. Graph, dT _o does not exceed the Omega _damage is one to exceed 11.3K, while the Omega _hsp is greater than 1 throughout the intervals indicated that (desirable conditions for cellular repair with no damage) Show.

Equation [8], when it is α = 0.1cm ^-1, 11.5 K of dT _o have shown that can be achieved with the total ultrasonic power 5.8 watts. This is easily achievable. Even if α is increased 2 or 3 times, the resulting power is still easily achievable. The volume of the region where the temperature rise is constant (that is, the volume corresponding to r = r _d = (4Dt _p ) ^1/2 ) is 0.00064 cc. This corresponds to a cube whose side is 0.86 mm.

This simple example demonstrates that focused ultrasound should be used to stimulate deep repair HSPs in the body along with easily achievable equipment:
Total ultrasonic power: 5.8 watts-17 watts Pulse time 0.5 seconds Pulse interval 5 seconds Total row duration (N = 10) To facilitate treatment of internal volumes greater than 50 seconds, the SAPRA system Can be used.

  The present invention contemplates the treatment of blood diseases such as sepsis, as well as treatment of surface tissue near or near the surface using laser light, etc., and treatment of deep tissue using, for example, focused ultrasound beams. doing. As indicated above, focused ultrasound treatment can be used on deep body tissues in addition to the surface, and can also be applied when treating blood. However, similar treatment options typically limited to surface treatments such as SDM and epithelial cells or treatment near the surface may cause blood disorders in areas accessible to blood through a relatively thin layer of tissue such as the earlobe. It is also contemplated that it should be used in treating

  Referring now to FIGS. 13 and 14, treatment of a blood disorder simply requires transmission of SDM or other electromagnetic radiation or ultrasound pulses to the earlobe 88, where other SDM or other energy The radiation source can travel through the earlobe tissue and into the blood flowing through the earlobe. It will be appreciated that this approach can be performed in other areas of the body where blood flow is relatively high and / or near the tissue surface, such as inside the fingertip, mouth or throat.

  Referring now to FIGS. 13 and 14, the earlobe 88 is shown adjacent to a clamping device 90 that is configured to transmit SDM radiation or the like. This may be due, for example, to one or more laser diodes 92 transmitting the desired frequency to the lobe 88 with the desired pulse and pulse train. For example, power may be provided by the lamp device 94. Alternatively, the lamp device 94 may be the actual source of laser light that is transmitted to the earlobe 88 through suitable optical elements and electronics. The clamping device 90 is only used to clamp on the patient's earlobe and cause the radiation to be constrained to the patient's earlobe 88. This can be done by mirrors, reflectors, diffusers and the like. This can be controlled by a control computer 96 operated by a keyboard 98 or the like. The system may also include a display and speaker 100 if necessary, for example, when the procedure is performed by an operator away from the patient.

  The proposed treatment with a train of electromagnetic or ultrasonic pulses has two major advantages over the initial treatment that incorporates either a single short pulse or a maintenance (long) pulse pulse. The first advantage is that short (preferably within one second) individual pulses in a row of cells such as HSP activation with a larger reaction rate constant than those operating on a longer (minute or hour) time scale. Activating the reset mechanism. A second advantage is that large heat spikes, where repeated pulses in therapy allow the cell repair system to more quickly overcome the activation energy barrier that separates the dysfunctional cellular state from the desired functional state. (Approx. 10,000). The net result is a “reduction in therapeutic threshold” in the sense that a lower applied average power and total applied energy can be used to achieve the desired treatment goal.

  While several embodiments have been described in detail for purposes of illustration, various modifications may be made without departing from the scope and spirit of the invention. Accordingly, the invention is not limited except as by the appended claims.

Claims (17)

A method of stimulating heat shock protein activation in a tissue comprising the steps of:
To provide a source of pulsed ultrasonic or electromagnetic radiant energy, and to provide a thermal time course that stimulates the cells of the target tissue to activate the heat shock protein without damaging the target tissue Applying pulsed ultrasonic or electromagnetic radiant energy to the target tissue.   The method of claim 1, wherein applying the radiant energy comprises raising the temperature of the target tissue by no more than 1 ° C. for a few minutes, but temporarily at least 10 ° C.   2. The method of claim 1, wherein providing electromagnetic energy comprises providing ultraviolet, microwave, radio frequency or laser light at a predetermined wavelength.   4. The method of claim 3, wherein the laser light has a wavelength between 530 nm and 1300 nm, a duty cycle of less than 10%, and a pulse length of 500 milliseconds or less.   The method of claim 4, wherein multiple laser light spots are applied simultaneously to the target tissue.   The method of claim 1, wherein the plurality of ultrasound beams are focused on the target tissue.   The method of claim 1, wherein applying radiant energy comprises inserting the device into a body cavity and using the device to apply pulsed ultrasonic or electromagnetic radiant energy to tissue.   The method of claim 7, wherein the device comprises an endoscope.   Applying the radiant energy is applying pulsed ultrasonic or electromagnetic radiant energy to an external region of the body, wherein the external region of the body is adjacent to the target tissue or external to the body The method of claim 1, comprising the step of having a blood supply near the surface of the region.   The method of claim 9, wherein the body region includes an earlobe and pulsed electromagnetic radiant energy is applied to blood flowing through the earlobe. A method of stimulating heat shock protein activation in a tissue comprising the steps of:
Providing a source of pulsed ultrasonic or electromagnetic radiant energy, and the target tissue temperature to stimulate the target tissue cells and activate heat shock proteins without damaging the target tissue Applying pulsed ultrasonic or electromagnetic radiant energy to the target tissue to provide a thermal time course that is only 1 ° C. or less over a minute but temporarily raised at least 10 ° C .;
Here, the step of applying radiant energy includes inserting the device into a body cavity and using the device to apply pulsed ultrasonic or electromagnetic radiant energy to tissue, or pulsed ultrasonic or electromagnetic Applying the radiant energy to an external region of the body, the external region of the body having a blood supply adjacent to the target tissue or near the surface of the external region of the body.   The method of claim 11, wherein providing electromagnetic energy comprises providing ultraviolet, microwave, radio frequency, or laser light at a predetermined wavelength.   13. The method of claim 12, wherein the laser light has a wavelength between 530 nm and 1300 nm, a duty cycle of less than 10%, and a pulse length of 500 milliseconds or less.   14. The method of claim 13, wherein multiple laser light spots are applied to the target tissue simultaneously.   The method of claim 11, wherein the plurality of ultrasound beams are focused on the target tissue.   The method of claim 11, wherein the device comprises an endoscope.   12. The method of claim 11, wherein the body region includes an earlobe and pulsed electromagnetic radiant energy is applied to blood flowing through the earlobe.