CN109562272A

CN109562272A - For providing the method that protectiveness is treated to biological tissue or fluid

Info

Publication number: CN109562272A
Application number: CN201780047506.XA
Authority: CN
Inventors: J·K·卢特鲁勒; B·W·L·马戈利斯; D·B·昌
Original assignee: Ojai Retinal Technology LLC
Current assignee: Ojai Retinal Technology LLC
Priority date: 2016-08-09
Filing date: 2017-07-28
Publication date: 2019-04-02
Also published as: AU2017308587A1; JP2019524179A; CA3030483A1; EP3496810A4; WO2018031255A1; BR112019001348A2; EP3496810A1

Abstract

It is a kind of provided to biological tissue or fluid the method that protectiveness is treated include to chronic progressive disease or with the risk for suffering from chronic progressive disease target tissue or target fluid apply impulsive energy source, with the therapeutic or prophylactic treatment target tissue or target fluid.The impulsive energy source has energy parameter, it is selected to that the target tissue or target rehydration temperature are increased to predetermined temperature in a short period of time, to obtain therapeutic or prophylactic effects, the average temperature rising of the target tissue or target fluid is held in or is lower than predeterminated level during longer period simultaneously, thus will not the permanent damage target tissue or target fluid.

Description

Method for providing protective treatment to biological tissue or fluid

Technical Field

The present invention relates generally to methods for treating biological tissue or fluids. In particular, the present invention relates to methods for providing a protective treatment to biological tissue or fluids having or at risk of a chronic progressive disease.

Background

Chronic Progressive Disease (CPD) is currently and increasingly becoming a healthcare challenge in the future. There are many such CPDs, including type II diabetes, Alzheimer's disease, Idiopathic Pulmonary Fibrosis (IPF), heart disease, and the like. The underlying cause of many diseases is unknown, and these diseases are either not treated or not optimally treated. Some of these diseases either end consistently in the short term or constitute a major public health problem due to increased prevalence.

These diseases are not only chronic but also progressive. Chronic progressive disease may have many root causes, including infection, inheritance, multifactorial, and immunity. Although CPDs have many different causes, they have substantial commonality. A uniform feature of all CPDs is the accumulation of abnormal intracellular proteins. Another common feature of all CPDs is increased cellular and organ dysfunction, leading to failure. Yet another common and unified feature of CPD is that cellular and organ dysfunction causes and contributes to chronic inflammation. These features of all CPDs are a vicious circle, leading to worsening of the disease over time.

Therefore, interruption of this circulation is critical to improving the course of the disease. One approach to treating CPD is gene therapy, which requires the identification and repair or replacement of defective genes that cause disease. However, for some CPDs, the genetic defect is unknown. For other CPDs, there may be many potential genetic defects that cause the same disease. For example, retinitis pigmentosa (retinitis pigmentosa) can be caused by any of over 150 different gene defects. This potential multiple fundamental deficiency makes gene therapy difficult.

Another approach to treating CPD is drug therapy, which generally attempts to target specific cellular proteins thought to be critical to the disease process, to inhibit or enhance their effects. However, there are 10, as there are an estimated 2000 different protein types in a typical cell⁶⁸⁰This potential interaction, and therefore successful, clinically effective targeted drug therapy without unacceptable side effects, is difficult.

Another method of treating CPD is non-specific anti-inflammatory therapy. These include various steroidal and non-steroidal anti-inflammatory agents and immunosuppressive agents. However, anti-inflammatory drugs have a number of disadvantages in CPD. Since they do not address the underlying cause of the disease, they must be used for a long period of time and have limited efficacy. The side effects and complications of treatment limit their utility due to their mode of action and the need for long-term use. Immunosuppressive drugs have the same limitations as anti-inflammatory drugs. However, since they alter the normal function of the immune system in addition to the disease process, they can cause further complications, including other disease syndromes and neoplasias. Radiation therapy, for example using x-ray radiation, is another method of treating CPD. It has similar effects to those of anti-inflammatory and immunosuppressive drugs. However, it can also cause more problematic side effects that worsen over time even after treatment is stopped, thus often making the radiation therapy unacceptable if long-term survival is expected.

Another newer approach to CPD treatment is to identify and inhibit regulatory proteins. Such managed protein therapies attempt to address the problems posed by genetic, pharmaceutical, and anti-inflammatory/immunosuppressive therapies by finding key and common proteins or enzymes for several disease states, regardless of root cause, and inhibiting them in various ways. Since a single regulatory protein may be central to the development of several disease conditions, such as various and other unrelated cancers, blocking this key protein may have broader therapeutic applications than more disease-targeted therapies. However, if the protein itself is targeted, management protein therapy also has the usual limitations of targeted drug therapy, with the additional problem that triggering compensatory mechanisms such as up-regulation lead to permanent insensitivity to drug action. Furthermore, management of protein therapy also has the general limitations of gene therapy if the mechanisms of transcription and translation that produce the protein are targeted. Such management protein therapies also have problems with targeted drug therapies as described above.

Stem Cell Transplantation (SCT) is another method of CPD treatment. SCT attempts to replace dead or dysfunctional tissue with new functional tissue by transplanting stem cells into the tissue or into the area surrounding the tissue. SCT is very complex and expensive, with significant risks and adverse therapeutic effects. Although of great public interest, SCT has been ineffective to date.

The existing methods for CPD treatment described above have limited success and utility, and therefore most CPDs are currently not treated or are only palliative or ineffective treatments. These treatments have limited success and utility due to practical limitations including unknown or multiple causes, cost, time, and non-physiological (unnatural and artificial) modes of action that, by definition, superimpose new drug-induced disease states on the CPD. Accordingly, the ideal treatment of CPD should be independent of root cause, physiological, and therefore not only effective but well tolerated without side effects, and capable of breaking the vicious CPD cycle by multiple points in the cycle including intervention directly distal to the major defect to achieve maximum efficacy. The present invention fulfills these needs and provides other related advantages.

Disclosure of Invention

The present invention relates generally to methods for providing protective treatment to biological tissue or fluids having or at risk of chronic progressive disease. The present invention applies a pulsed energy source to a biological tissue or fluid to raise the temperature of the target tissue or fluid and stimulate activation of heat shock proteins, thereby promoting protein repair without damaging the tissue.

According to the present invention, a pulsed energy source is provided having energy parameters including wavelength or frequency, duty cycle (duty cycle) and pulse train duration (pulse train duration). The pulsed energy source may comprise a laser, microwave, radio frequency or ultrasound. The energy parameter is selected to warm the target tissue or body fluid to 11 ℃, typically between 6 ℃ and 11 ℃, at least during application of the pulsed energy source to the target tissue or body fluid, to achieve a therapeutic or prophylactic effect. The average temperature rise of the tissue or target fluid is maintained at or below a predetermined level over a period of minutes so as not to permanently damage the target tissue or target fluid. For example, the average temperature rise of the target tissue or target fluid can be maintained at 6 ℃ or less over a period of minutes. Typically, the average temperature rise of the target tissue or target fluid is maintained at about 1 ℃ or less over a period of several minutes, e.g., 6 minutes.

The pulsed energy source may comprise radio frequency. The radio frequency is typically between 3 and 6 megahertz (MHz) and has a duty cycle between 2.5% and 5% and a pulse train duration between 0.2 and 0.4 seconds. The radio frequency may be generated by a device having a coil radius between 2 and 6 millimeters and between 13 and 57 ampere turns.

When the pulsed energy source comprises a microwave frequency, the frequency is typically between 10 and 20 gigahertz (GHz), the pulse train duration is between 0.2 and 0.6 seconds, and the duty cycle is between 2% and 5%. The microwaves may have an average power between 8 and 52 watts.

When the pulsed energy source is a pulsed light beam, the light beam may have a wavelength between 530 nanometers to 1300 nanometers, a duty cycle of less than 10%, and a pulse train duration between 0.1 and 0.6 seconds. Preferably, the pulsed light beam has a wavelength between 800 nanometers and 1000 nanometers, and a power between 0.5 and 74 watts.

When the pulsed energy source comprises pulsed ultrasound, it typically has a frequency between 1MHz and 5MHz, a column duration between 0.1 and 0.5 seconds, and a duty cycle between 2% and 10%. The ultrasound may have a power between 0.46 and 28.6 watts.

The target tissue or target fluid may be determined to have or be at risk of having a chronic progressive disease. Applying the pulsed energy source to the target tissue or target fluid having or at risk of having a chronic progressive disease to therapeutically or prophylactically treat the target tissue or target fluid. The energy parameters of the pulsed energy source may be selected to absorb 20 to 40 joules of energy per cubic centimeter of the target tissue or target fluid. To apply the pulsed energy source, a device may be inserted into the body cavity to apply the pulsed energy source to the target tissue or target fluid. Alternatively or additionally, the pulsed energy source is directed to an exterior of the body adjacent to the target tissue or having a supply of target bodily fluid proximate a surface of the exterior of the body. The pulsed energy source may be applied to a plurality of target tissue regions. Adjacent target tissue regions are separated by at least a predetermined distance to avoid thermal tissue damage.

It is believed that the method of the present invention provides beneficial effects by selectively and controllably raising the temperature of the target tissue or fluid to a predetermined temperature range during short periods of time while maintaining the average temperature rise of the tissue at a predetermined temperature during longer periods of time. These effects can be caused by inducing a heat shock response to increase the number or activity of heat shock proteins in body tissues or fluids in response to infection or other abnormalities. The present invention performs this method in a controlled manner so as not to damage or destroy the tissue, fluid or area of the body being treated.

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

Drawings

The drawings are intended to illustrate the invention. In these drawings:

FIG. 1 shows a schematic view of a system for generating a pulsed energy source in the form of a laser beam in accordance with the present invention;

FIG. 2 shows a schematic view of optics used to generate a laser geometry in accordance with the present invention;

FIG. 3 shows a schematic view of an alternative embodiment of a system for generating a laser beam to treat tissue and fluids in accordance with the present invention;

FIG. 4 shows a schematic view of another embodiment of a system for generating a laser beam to treat tissue in accordance with the present invention;

FIG. 5 shows a top view of an optical scanning mechanism used in accordance with the present invention;

FIG. 6 shows a partially exploded view of the optical scanning mechanism of FIG. 5 to illustrate various components thereof;

FIG. 7 illustrates controlled shifting of the irradiation of laser spots to treat an exemplary geometric pattern grid of a target tissue in accordance with the present invention;

FIG. 8 shows a schematic view of a geometric object in the form of a line controllably scanned for treatment of a target tissue in accordance with the present invention;

FIG. 9 shows a schematic view similar to FIG. 8 but showing the rotation of the geometric wire or strip to treat a region in accordance with the present invention;

FIGS. 10 and 11 show graphs of the average power of a laser source versus the source radius and pulse train duration of the laser;

FIGS. 12 and 13 show graphs of temperature versus time for the decay of the laser source radius and wavelength;

14-17 show graphs of peak ampere-turns for different radio frequencies, duty cycles, and coil radii;

FIG. 18 shows a graph of the time of decay of temperature rise versus radius of the RF coil;

FIGS. 19 and 20 show graphs of average microwave power versus microwave frequency and pulse train duration;

FIG. 21 shows a graph of time of temperature decay for different microwave frequencies;

FIG. 22 shows a graph of average ultrasound source power versus frequency and pulse train duration;

figures 23 and 24 show graphs of the time of temperature decay for different ultrasound frequencies;

FIG. 25 shows a graph of the volume of the focal heating zone versus ultrasonic frequency;

FIG. 26 is a graph showing a comparison of the temperature of the ultrasonic energy source with the pulse duration equation;

figures 27 and 28 show graphs of the magnitude of the log of the injury and HSP activation Arrhenius integration as a function of temperature and pulse duration; FIG. 29 shows a schematic view of a light generating unit having a light pipe extending therefrom for generating a timed pulse sequence in accordance with the present invention;

FIG. 30 shows a cross-sectional view of a photostimulation delivery device delivering electromagnetic energy to target tissue according to the present invention;

FIG. 31 shows a cutaway and schematic view of the end of an endoscope being inserted into the nasal cavity and treating tissue therein in accordance with the present invention;

FIG. 32 shows a schematic and partial cut-away view of a bronchoscope extending through the trachea and into the bronchi of the lungs and providing therapy thereto in accordance with the present invention;

FIG. 33 shows a schematic view of a colonoscope providing light stimulation to an intestinal or colon region of the body in accordance with the present invention;

FIG. 34 shows a schematic view of an endoscope being inserted into the stomach and providing treatment thereto in accordance with the present invention;

FIG. 35 shows a partially cut-away perspective view of a capsule endoscope used in accordance with the present invention;

FIG. 36 shows a schematic view of pulsed high intensity focused ultrasound for treating tissue within a body in accordance with the present invention;

FIG. 37 shows a schematic view of treatment provided to a patient's bloodstream through an earlobe in accordance with the present invention;

FIG. 38 shows a cross-sectional view of a stimulation therapy device of the present invention used in delivering light stimulation to the blood through the earlobe in accordance with the present invention; and

fig. 39 shows a schematic and perspective view of a device for treating multiple areas or the entire body of an individual in accordance with the present invention.

Detailed Description

The invention as fully described and illustrated herein resides in a method and system for providing a protective treatment to a biological tissue or fluid having or at risk of having a chronic progressive disease. In accordance with the present invention, the pulsed energy source has energy parameters including wavelength or frequency, duty cycle, and pulse train duration selected to raise the temperature of the target tissue or target fluid to 11 degrees celsius for a short period of seconds or less while maintaining the average temperature rise of the tissue or target fluid at or below a predetermined level over a period of minutes so as not to permanently damage the target tissue or target fluid. Applying the pulsed energy source to the target tissue or target fluid determined to have or at risk of having a chronic progressive disease. This determination may be made before imaging, serology, immunology or other abnormalities are detectable or may be performed prophylactically. This determination can be achieved by ascertaining whether the patient is at risk for a chronic progressive disease. Alternatively or additionally, the results of the patient's examination or test may be abnormal. Specific tests, such as genetic tests, may be performed to confirm that the patient is at risk for a chronic progressive disease.

It is believed that the mechanism by which the present invention treats biological tissues or fluids therapeutically or prophylactically is through stimulation of heat shock protein activation in the target tissue or fluid. Heat Shock Proteins (HSPs) are ubiquitous in a highly conserved family of enzymes found in all cells of all organisms. This can be up to 40% of all proteins present in a given cell. HSPs are active and vital in maintaining normal cellular function and homeostasis. HSPs have a number of key functions, one of which is the protection of cells from any type of lethal injury and the repair of sublethal (sublethal) injury.

While chronic inflammation is pathological and destructive, acute inflammation can be reparative. Acute inflammation can occur in response to acute injury. Common injuries requiring repair are often associated with cellular and tissue damage such as wounds. Depending on the severity of the injury and the functional sensitivity of the tissue, loss of critical function may result despite wound repair. Incomplete repair or sustained or repeated injury may lead to chronic inflammation as in CPD.

Normal health is maintained by continuously monitoring and repairing the complex physiological processes of defective protein and the development of potential threats such as bacteria, viruses and neoplasms. These normal physiological processes and their effects are ideal because good health and function are the result of their normal function. While the normal function of these physiological processes is ideal, such steady state processes are not always perfectly effective in themselves. Potential threats and anomalies may escape detection or exceed repair capabilities. Failure to monitor and respond may result from a number of causes, including immunosuppression due to disease, evasion of detection by cryptic antigen stimulation (e.g., occurring in certain cancers and retroviruses), and onset and progression at levels below that of symptom recognition and activation.

HSPs are the first step in the acute inflammatory process. Activation of HSPs by threat causes a series of subsequent events leading to improved cellular function, reduced chronic inflammation, and reparative immune modulation. Potent HSP activation preserves the life of cells and normalizes cellular functions, also known as homotrophy. Sudden and severe stimulation is the most effective stimulator of syntrophic HSP activation. Slow-progressing and chronic stimulation is not a potent activator of HSP response. Thus, CPD does not stimulate the repair response of HSP activation. In some CPDs, such as diabetes and alzheimer's disease, HSP function itself may become abnormal.

However, in general, HSPs normalize cellular function independently of the cause of abnormalities by identifying and repairing abnormal cellular proteins without regard to the cause of their abnormality. HSPs have the ability to restore each protein to its correct state or eliminate irreparable proteins for replacement. Since HSP responses are physiological and therefore perfect, and have no adverse effects, repairing the disruption regardless of the cause of the disruption, the HSP's repair response is well suited for the disease process. Therefore, syntrophic HSP activation is a non-specific trigger for disease-specific repair.

The inventors have found that inducing acute but sub-lethal cellular hyperthermia by electromagnetic radiation stimulates HSP activation without cell or tissue damage is feasible. Thus, in the absence of cell death or tissue damage, a cascade of physiological repair and co-nourishment of the acute inflammatory response can be triggered without adverse therapeutic effects. Acute inflammation induced without tissue damage may be considered "as if" acute inflammation. That is, the homeostatic cellular hyperthermia is able to elicit a complete and only beneficial acute inflammatory response, "as if it were caused by tissue damage, but without tissue damage. It has been found that the safest and most effective stimulation of homeotropic HSP activation is by pulsed electromagnetic radiation (PEMR). The pulsing allows for a significant increase in the abruptness and severity of the threat stimulus without killing the target cells, thereby maximizing HSP activation in a homotrophic healing response. Different types of PEMRs are best suited for different biological applications, including light, laser, radio waves, and microwaves and ultrasound.

The eye is the most functionally sensitive organ in the body. There are several CPDs that affect the retina and they often share the typical characteristics of CPD. Accordingly, the CPD of the retina can serve as a model of the CPD elsewhere in the body. Clinical experience in a large number of patients over the years has shown that PEMRs in the form of low intensity/high density sub-threshold diode pulsed laser therapy (SDM) have proven effective in treating, preventing, slowing, reversing or arresting the progression of each of the major chronic progressive diseases of the retina, regardless of cause. These include age-related, genetic, metabolic and unknown diseases with widely varying genotypes and phenotypes (phenotypes). Despite the thermal sensitivity of the retina, SDM does this without any known adverse therapeutic effects due to the selection of operational parameters for PEMR, and is therefore performed in a completely safe manner.

With respect to traditional retinal photocoagulation, a physician must deliberately create retinal lesions as a prerequisite to a therapeutically effective treatment. However, the inventors speculate that the therapeutic changes produced by the conventional photocoagulation-induced Retinal Pigment Epithelium (RPE) cytokines (cytokines) come from cells at the edges of the conventional laser burns that are affected by the laser irradiation but are not killed by the laser irradiation. The inventors created an energy parameter that creates a "true subthreshold photocoagulation" that is invisible and includes laser treatment that is not recognizable by any known method (e.g., FFA, FAF, retrograde FAF, or even DS-OCT) and absolutely does not produce retinal damage that is detectable by any means at the time of treatment or at any time later by any known detection means, but still produces the benefits of traditional retinal photocoagulation. This is discussed in U.S. publication No. 2016/0346126a1, the contents of which are incorporated herein by reference.

Various parameters are determined to achieve true subthreshold effective photocoagulation, including providing sufficient power to produce effective treatment, but not so high as to cause tissue damage or destruction. It has been found that a low duty cycle 810 nanometer laser beam intensity or power of between 100 watts per square centimeter and 590 watts is effective and safe. For a 810 nm micropulsed diode laser, a particularly preferred intensity or power of the laser beam is about 250 to 350 watts per square centimeter.

The power limitations of current micro-pulsed diode lasers require longer irradiation durations, but it is important that the generated heat be able to dissipate towards the non-irradiated tissue at the edge of the laser spot in order to avoid damaging or destroying cells or tissue. It has been found that the radiation beam of a 810 nm diode laser should have an illumination envelope of 500 milliseconds or less, preferably about 100 to 300 milliseconds. If the micropulsed diode laser is changed to a higher power, the irradiation duration can be reduced accordingly. It has been found that invisible phototherapy or true subthreshold photocoagulation in accordance with the present invention can be performed at various laser wavelengths, for example, ranging from 532 nanometers to 1300 nanometers. The use of different wavelengths may affect the preferred intensity or power of the laser beam and the duration of the illumination envelope so as not to damage the retinal tissue, but still achieve a therapeutic effect. Typically, the laser pulse is less than 1 millisecond in duration, and typically between 50 microseconds and 100 microseconds in duration.

Another parameter of the invention when using laser light is the duty cycle, or the frequency of the micro-pulse train or the length of the thermal relaxation (thermal relaxation) time between successive pulses. It has been found that the use of a duty cycle of 10% or higher can increase the risk of lethal cell injury. Thus, a duty cycle of less than 10% and preferably about 5% or less is used, as this parameter has been shown to provide a sufficient heat rise in treatment that is below the level expected to produce lethal cell damage. The smaller the duty cycle, the longer the illumination envelope duration may be. For example, if the duty cycle is less than 5%, the illumination envelope duration may exceed 500 milliseconds in some cases.

Thus, the following key parameters have been found to create harmless, true subthreshold photocoagulation in retinal tissue in accordance with the present invention:

a) a light beam having a wavelength of at least 532 nm and preferably between 532 nm and 1300 nm;

b) a low duty cycle, e.g., less than 10% and preferably 5% or less;

c) small spot size to minimize heat accumulation and ensure uniform heat distribution within a given laser spot, thereby maximizing heat dissipation; and

d) sufficient power to produce retinal laser irradiation between 18 and 55 times MPE to produce an RPE temperature rise of 7 ℃ to 14 ℃ and 100 to 590W/CM²Retinal irradiance in between.

By using these above parameters, a non-harmful but therapeutically effective true subthreshold or invisible photocoagulation phototherapy treatment is achievable, which has been found to yield the benefits of conventional photocoagulation phototherapy but avoids the disadvantages and complexities of conventional phototherapy. The adverse therapeutic effects are completely eliminated and the functional retina is retained rather than sacrificed. Furthermore, the entire retina may be exposed to the pulsed energy source of the present invention to allow for complete, rather than local or partial prophylactic and therapeutic treatment of an eye suffering from a retinal disease.

In the retina, clinical benefit of SDM is produced by sub-pathologic photothermal RPE HSP activation. In dysfunctional RPE cells, HSP stimulation by SDM results in normalized cytokine expression and thus improved retinal structure and function. HSP stimulation in normal cells often has no significant clinical effect, as normally functioning cells do not require repair. The "pathological selectivity" of the near-infrared laser effect, e.g., SDM, affects diseased cells of various cell types without affecting normal cells consistent with clinical observations of SDM. This function is critical for the applicability of SDM for early and prophylactic treatment of eyes with chronic progressive disease as well as eyes with mild retinal abnormalities and mild dysfunction. Although SDM is safe, the clinical effects of SDM are significant and profound. For example, SDM reduces the rate of progression of diabetic retinopathy by 85% (P0.0001) and the rate of progression of age-related macular degeneration by 95% (P <0.0001), improving the optic nerve function of glaucoma (P0.001) and the visual field of glaucoma and all retinal diseases including retinitis pigmentosa (P0.0001).

Referring now to FIG. 1, a schematic diagram of a system for implementing the method of the present invention is shown. The system, generally designated by reference numeral 10, includes a laser console 12, such as a 810 nanometer near infrared micro-pulse diode laser in the preferred embodiment. The laser generates a laser beam that is passed through optical means, such as an optical lens or mask, or a plurality of optical lenses and/or masks 14, as desired. The laser projector optics 14 deliver the shaped beam to an on-axis wide-area untouched digital optical viewing system/camera 16 to project the laser beam light onto the patient's eye 18, or other biological target tissue or body fluid as detailed herein. It will be appreciated that block 16 may represent both a laser beam projector and a viewing system/camera, which in practice may comprise two distinct components when in use. The viewing system/camera 16 provides feedback to a display monitor 20, which may also include necessary computerized hardware, data input and control, etc., to operate the laser 12, optics 14, and/or projection/viewing assembly 16.

Referring now to FIG. 2, in one embodiment, a laser beam 22 is passed through a collimator lens 24 and then through a mask 26. In a particularly preferred embodiment, mask 26 comprises a diffraction grating. Mask/diffraction grating 26 produces a geometric object, or more typically, a geometric pattern made up of multiple laser spots or other geometric objects generated simultaneously. This is represented by a plurality of laser beams 28. Alternatively, the plurality of laser spots may be generated by a plurality of fiber optic lines. Both methods of generating laser spots allow for the simultaneous creation of extremely large numbers of laser spots over an extremely wide treatment field, for example, consisting of the entire retina. In practice, a very high number of laser spots (perhaps hundreds or even thousands or more) may cover the entire fundus and the entire retina, including the macula and fovea, retinal blood vessels, and the optic nerve. The method of the present invention aims to better ensure complete and comprehensive coverage and treatment of a target area, which may include the retina, without leaving any part of the retina behind by the laser, thereby improving vision.

By using optical features with feature sizes comparable to the wavelength of the laser light employed, for example by using diffraction gratings, it is possible to exploit quantum mechanical effects, which allow for the simultaneous application of very large numbers of laser spots to very large target areas. The individual spots produced by such diffraction gratings all have similar optical geometries as the input beam, with each spot having minimal power variation. The result is multiple laser spots with sufficient irradiance simultaneously producing harmless but effective therapeutic applications over a large target area. The present invention also contemplates the use of other geometric objects and patterns generated by other diffractive optical elements.

Laser diffraction through mask 26 produces a periodic pattern at a distance from mask 26, as shown by laser beam 28 in FIG. 2. A single laser beam 22 is thus formed into multiple (up to hundreds or even thousands) of individual laser beams 28 to create a desired pattern of spots or other geometric objects. These laser beams 28 may be passed through additional lenses, collimators, etc. 30 and 32 to transmit the laser beams and form the desired pattern on the patient's retina. Such additional lenses, collimators, etc. 30 and 32 may also convert and redirect the laser beam 28 as desired.

Any pattern may be constructed by controlling the shape, spacing, and pattern of the optical mask 26. The pattern and the illumination spot can be created and modified arbitrarily, as required by the application requirements of experts in the field of optical engineering. Photolithography techniques, particularly those developed in the field of semiconductor manufacturing, can be used to create simultaneous geometric patterns of spots or other objects.

Although hundreds or even thousands of simultaneous laser spots may be generated and created and formed into a pattern to be applied to tissue, the number of treatment spots or beams that may be used simultaneously in accordance with the present invention is limited due to the requirement that the tissue not be overheated. Each individual laser beam or spot needs to be effective at a minimum average power during the column duration. At the same time, however, the tissue cannot exceed a certain temperature rise without being damaged. For example, for a 810 nm wavelength laser, the number of simultaneous spots generated and used can range from only 1 up to about 100 when using a 0.04 (4%) duty cycle and a total column duration of 0.3 seconds (300 milliseconds).

The absorption of water increases with increasing wavelength, resulting in heating over a long path length through the anterior vitreous of the retina. For shorter wavelengths, such as 577 nanometers, the absorption coefficient of melanin of the RPE may be higher, and thus the laser power may be lower. For example, at 577 nm, the power can be reduced by a factor of 4 for the present invention to be effective. Accordingly, when using a 577 nm wavelength laser, it is possible to have only a single laser spot or up to about 400 laser spots without damaging or injuring the eye or other tissue. The present invention may use multiple simultaneously generated treatment beams or spots, e.g., tens or even hundreds, because the parameters and methods of the present invention create a therapeutically effective but non-destructive and non-permanent lesion treatment.

FIG. 3 schematically illustrates a system for coupling a plurality of light sources to the pattern generating optical subassembly described above. Specifically, system 10' is similar to system 10 described above in FIG. 1. The primary difference between the alternative system 10' and the earlier described system 10 is the inclusion of a plurality of laser consoles 12, the outputs of which are each input into a fiber coupler 34. The fiber coupler produces a single output that is delivered to the laser projector optics 14 as described in earlier systems. Coupling multiple laser consoles 12 into a single fiber is accomplished by fiber couplers 34 as known in the art. Other known mechanisms for combining multiple light sources are available and can be used in place of the fiber optic couplers described herein.

In this system 10', the plurality of light sources 12 follow similar paths as described earlier in system 10, namely collimation, diffraction, re-collimation, and directing into the retina by a directing mechanism. In this alternative system 10', the diffractive elements act in a different manner than described earlier, depending on the wavelength of light passed through, resulting in a slightly varying pattern. The variation is linear with the wavelength of the diffracted light source. In general, the difference in diffraction angles is small enough that different overlapping patterns can be directed along the same optical path through the directing mechanism 16 toward the retina 18 for treatment. A slight difference in diffraction angle will affect how the guide pattern achieves coverage of the retina.

Since the resulting pattern will vary slightly for each wavelength, the sequential shift to achieve full coverage will be different for each wavelength. This sequential shift can be implemented in two modes. In the first mode, light of all wavelengths is applied simultaneously without the same coverage. An offset guide pattern is used that achieves full coverage for one of the plurality of wavelengths. Thus, while light of a selected wavelength achieves complete coverage of the tissue region to be treated, application of other wavelengths achieves incomplete or overlapping tissue coverage. The second mode sequentially applies varying or different wavelengths of light sources with appropriate guide patterns to achieve complete coverage of tissue for that particular wavelength. This mode excludes the possibility of simultaneous treatment using multiple wavelengths, but allows the optical method to achieve the same coverage for each wavelength. This avoids incomplete or overlapping coverage for arbitrary wavelengths of light.

These patterns may also be mixed and matched. For example, two wavelengths may be applied simultaneously, one wavelength achieving full coverage and the other achieving incomplete or overlapping coverage, followed by a sequential application of a third wavelength and achieving full coverage.

Fig. 4 schematically shows another alternative embodiment of the inventive system 10 ". This system 10 "is configured substantially the same as the system 10 shown in FIG. 1. The main difference is the inclusion of a plurality of pattern generating subassembly channels tuned to the particular wavelength of the light source. A plurality of laser consoles 12 are arranged in parallel, each directly leading to its own laser projector optics 14. The laser projector optics of each channel 38a, 38b, 38c include a collimator 24, a mask or diffraction grating 28, and a re-collimator 30, 32, as described above in connection with fig. 2-the entire set of optics is tuned for the particular wavelength generated by the corresponding laser console 12. The outputs of the various groups of optics 14 are then directed to a beam splitter 36 to be combined with other wavelengths. As known to those of ordinary skill in the art, a reverse-use beam splitter may be used to combine multiple beams into a single output.

The combined channel output from the final beamsplitter 36c is then directed through the camera 16, which applies a directing mechanism to allow complete coverage of the retina 18.

In system 10 ", the optical elements of each channel are tuned to produce a precise specific pattern for the wavelength of the channel. Thus, when all channels are combined and properly aligned, a single guide pattern can be used to achieve complete coverage of the retina for all wavelengths.

The system 10 "may use as many channels 38a, 38b, 38c, etc. and beam splitters 36a, 36b, 36c, etc. as the wavelengths of light used in the treatment.

Implementations of system 10 "may utilize different symmetries to reduce the number of alignment constraints. For example, the proposed grid pattern is periodic in two dimensions and directed along two dimensions to achieve full coverage. Thus, if the pattern and designation of each channel is the same, the actual pattern of each channel will not need to be aligned for the same guide pattern to achieve complete coverage for all wavelengths. Only optical alignment of the channels will be required to achieve effective combining.

In system 10 ", the channels begin with a light source 12, which may be from an optical fiber as in other embodiments of the pattern generation subassembly. The light source 12 is directed to an optical assembly 14 to collimate, diffract, re-collimate and direct to the beam splitter, which combines the channels with the primary output.

The field of photobiology indicates that different biological effects can be obtained by exposing target tissue to laser light of different wavelengths. The same effect can also be obtained by applying a plurality of lasers with different or the same wavelength sequentially and successively at variable intervals and/or with different radiant energies. The present invention contemplates the simultaneous or sequential application of multiple laser, light or radiation wavelengths (or modes) to maximize or customize the desired therapeutic effect. This approach also minimizes potential harmful effects. The optical methods and systems shown and described above provide for the simultaneous or sequential application of multiple wavelengths.

Typically, the system of the present invention comprises a guidance system to ensure a complete and comprehensive treatment by light stimulation. A fixation/tracking/registration system consisting of a fixation target, tracking mechanism and operatively linked to the system may be incorporated into the present invention.

In certain preferred embodiments, the geometric patterns of simultaneous laser spots are sequentially offset to achieve fusion and complete treatment of the target tissue. This is performed in a time-saving manner by arranging a plurality of spots over the target tissue at once. This simultaneous pattern of spots is sequentially scanned, shifted or redirected as an overall array to cover the entire target tissue during a single treatment.

This may be performed in a controlled manner by using the optical scanning mechanism 40. Fig. 5 and 6 show an optical scanning mechanism 40 that may be used in the form of a MEMS mirror having a substrate 42 with electronically actuated controls 44 and 46 for tilting and moving a mirror 48 when power is applied to and removed from the electronically actuated controls. Application of power to the controllers 44 and 46 moves the mirror 48, thereby causing the simultaneous pattern of laser spots or other geometric objects reflected thereon to correspondingly move over the target tissue of the patient. This may be performed in an automated manner, for example, by using an electronic software program (program) to adjust the optical scanning mechanism 40 until the target tissue is completely covered or at least a portion of the target tissue in need of treatment is exposed to phototherapy. The optical scanning mechanism may also be a small beam diameter scanning galvanometer system, or similar systems, such as those distributed by Thorlabs, Inc. Such a system is capable of scanning the laser in a desired offset pattern.

Since the parameters of the present invention determine that the applied radiant energy or laser is not destructive or damaging, the geometric patterns of the laser spots, for example, can be superimposed without damaging the tissue or forming any permanent damage. However, in certain preferred embodiments, as shown in FIG. 7, the pattern of spots is shifted on each shot, thereby creating a space between shots from the previous shot to allow for heat dissipation and prevent the potential for thermal or tissue damage. Thus, as shown in fig. 7, the pattern, which is shown as a grid of 16 spots, is shifted per shot so that the laser spot occupies a different space than the previous shot. It should be understood that the schematic use of circles or open dots and solid dots is for illustrative purposes only to illustrate the prior and subsequent illumination of areas with spot patterns according to the present invention. The spacing of the laser spots prevents overheating and damaging of the tissue. It will be appreciated that this occurs until the entire target tissue has received phototherapy or until the desired effect is achieved. This may be performed, for example, by a scanning mechanism, such as by applying a static electric torque to the micro-machined mirror, as shown in fig. 5 and 6. By using small laser spots (preventing heat build-up) separated by non-illuminated areas in combination with a grid with a large number of spots on each side, it is possible to treat large target areas very quickly and non-invasively with short illumination durations.

By rapidly and sequentially repeating the entire simultaneously applied reorientation or shifting of the grid array of spots or geometric objects, complete coverage of the target tissue (e.g., human retina) can be rapidly achieved without thermal tissue damage. Depending on the laser parameters and the desired application, this offset can be determined by an algorithm to ensure the fastest treatment time and minimal risk of damage due to thermal tissue.

For example, the following is modeled by using the fraunhofer Approximation. Using a 9x9 square mask, an aperture radius of 9 microns, an aperture pitch of 600 microns, using an 890 nm wavelength laser, a mask-lens spacing of 75 mm, and a secondary mask size of 2.5 mm x2.5 mm, the following parameters will produce a grid of 19 spots on each side spaced 133 microns with a spot size radius of 6 microns. Given the desired area side length "a", given the output pattern spots "n" per square edge, the spacing between spots "R", the spot radius "R" and the desired square side length "a" to the treatment area, the number of shots "m" (coverage for the fused small spot application) required for treatment can be given by:

through the arrangement, the operation times m of treating different irradiation fields can be calculated. For example, a 3 mm x3 mm area favorable for treatment would require 98 deflection operations, requiring a treatment time of about 30 seconds. Another example is a 3cm x 3cm area. For such a large treatment area, a larger secondary mask size of 25 mm x25 mm may be used, resulting in a treatment grid of 190 spots per side spaced 133 microns with a spot size radius of 6 microns. Since the secondary mask size is increased by the same factor as the required treatment area, the number of shift operations of about 98 and thus the treatment time of about 30 seconds is constant. A field size of 3 mm would, for example, allow treatment of the macula of the entire person in a single irradiation, facilitating the treatment of common blinding conditions such as diabetic macular edema and age-related macular degeneration. Performing all 98 sequential shifts will ensure complete coverage of the macula.

Of course, the number and size of spots generated in a simultaneous pattern array is variable and varied, so that the number of sequential offset operations required to complete a treatment can be easily adjusted according to the treatment requirements of a given application.

Furthermore, with the help of small holes employed in the diffraction grating or mask, quantum mechanical behavior can be observed, which allows arbitrary distribution of the laser input energy. This would allow the generation of multiple spots in any geometric shape or pattern, for example in a grid pattern, lines or any other desired pattern. Other methods of generating the geometry or pattern, such as using a plurality of optical fibers or microlenses, may also be used in the present invention.

Referring now to fig. 8 and 9, instead of using a geometric pattern of small laser spots, the present invention contemplates the use of other geometric objects or patterns. For example, a single laser line 50 may be created that is continuous or formed by a series of closely spaced spots. The line may be sequentially scanned over the area using an offset optical scanning mechanism, as indicated by the downward arrow in fig. 8. Referring now to fig. 9, the same geometric objects of line 50 may be rotated, as indicated by the arrows, to create a circular phototherapy field. However, a potential negative effect of this approach is that the central area will be repeatedly irradiated and may reach unacceptable temperatures. However, this disadvantage can be overcome by increasing the time between irradiations or by forming voids in the line so that the central region is not irradiated.

Power limitations in current micro-pulsed diode lasers require a rather long illumination duration. The longer the irradiation time, the more important the ability of the center-spot heat sink to the non-irradiated tissue at the edge of the laser spot. Accordingly, the micro-pulsed laser beam of a 810 nm diode laser should have an illumination envelope duration of 500 milliseconds or less, and preferably about 300 milliseconds. Of course, if the micro-pulse diode laser is changed to a higher power, the irradiation duration should be reduced accordingly.

In addition to the power limit, another parameter of the present invention is the duty cycle, or the frequency of the micro-pulse train, or the length of the thermal relaxation time between successive pulses. It has been found that the use of 10% duty cycle or higher duty cycles of a micro-pulsed laser adjusted to deliver similar irradiance at similar MPE levels significantly increases the risk of lethal cell damage. However, a duty cycle of less than 10% and preferably 5% or less indicates adequate heat rise and treatment at the level of MPE cells used to stimulate a biological response, but remains below the level expected to produce lethal cell damage. However, the lower the duty cycle, the illumination envelope duration increases, and in some cases may exceed 500 milliseconds.

Each micropulse lasts a fraction of a millisecond, typically between 50 microseconds and 100 microseconds in duration. Thus, for illumination envelope durations of 300 to 500 milliseconds, and less than a 5% duty cycle, there is a significant amount of time between micropulses to allow for thermal relaxation times between successive pulses. Typically, a delay in thermal relaxation time of between 1 and 3 milliseconds, preferably about 2 milliseconds, is required between successive pulses. For adequate treatment, the cells are typically subjected to between 50 and 200 laser shots or impacts, and preferably between 75 and 150 at each location. With a relaxation or separation time of 1 to 3 milliseconds, the total time to treat a given region (or in particular the location of the target tissue exposed to the laser spot) according to the above embodiments is on average between 200 and 500 milliseconds. Thermal relaxation times are required to avoid overheating the cells in the location or spot and to prevent damage or destruction of the cells.

The inventors have found that treatment of patients with age-related macular degeneration (AMD) according to the invention may slow the progression or even stop the progression of AMD. Further evidence for this restorative therapeutic effect is that the inventors found that treatment could uniquely reduce the risk of vision loss in AMD due to choroidal neovascularization (chorodalneovascularization) by up to 90%. After treatment according to the invention, most patients have seen a significant improvement in mid-dynamic function logMAR visual acuity versus contrast visual acuity, some experiencing better vision. This is believed to act by targeting, maintaining and "normalizing" (toward normal) the function of the Retinal Pigment Epithelium (RPE).

While systemic diabetes persists, treatment in accordance with the present invention has also been demonstrated to prevent or reverse the manifestation of diabetic retinopathy disease states without the damage or adverse effects associated with treatment. The inventors' studies indicate that the restorative effect of the treatment may uniquely reduce the risk of progression of diabetic retinopathy by 85%. On this basis, it is assumed that the present invention may function by inducing a restoration to more normal cell functions and cytokine expression in RPE cells affected by diabetes, similar to clicking a "reset" button of an electronic device to restore factory default settings.

Based on the above information and studies, SDM treatment can directly affect cytokine expression and Heat Shock Protein (HSP) activation in target tissues, particularly in the Retinal Pigment Epithelium (RPE) layer. The inventors have noted that whole retina and whole macula SDMs reduce the rate of progression of many retinal diseases, including severe nonproliferative and proliferative diabetic retinopathy, AMD, DME, and the like. The known therapeutic benefits of individuals with these retinal diseases, combined with the absence of known adverse therapeutic effects, allow for early and prophylactic treatment, liberal application, and retreatment to be considered, if necessary. This theory of replacement also suggests that the present invention is applicable to many different types of RPE-mediated retinal diseases. Indeed, the inventors have recently discovered that whole-macula 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, conus rod retinal degeneration, and Stargardt's disease (no other treatment previously found to do so).

Currently, retinal imaging and visual acuity testing guide the management of chronic progressive retinal disease. Since tissue and/or organ structural damage and vision loss are late stage disease manifestations, treatment initiated at this time must be intensive, often prolonged and expensive, and often fails to improve visual acuity and rarely restores normal vision. Since the present invention has proven to be an effective treatment for several retinal diseases without adverse therapeutic effects, and because of its safety and effectiveness, it is often useful to treat the eye to prophylactically prevent or delay the onset or symptoms of retinal diseases or as a prophylactic treatment for such retinal diseases. Any treatment that improves retinal function and thus improves health should also reduce disease severity, progression, adverse events, and vision loss. By initiating treatment early, before pathological structural changes, and maintaining the benefits of treatment through conventional functionally-guided re-treatment, structural degeneration and vision loss may therefore be delayed (if not prevented). Even a less severe reduction in the rate of disease progression at an early stage can lead to a long-term significant reduction in the complications of vision loss. By alleviating the consequences of major deficits, the course of the disease can be reduced, progression slowed, and complications and visual loss reduced. This is reflected in the inventors' studies, where treatment was found to reduce the risk of progression of diabetic retinopathy and vision loss by 85% and to reduce the risk of progression of AMD and vision loss by 80%.

According to one embodiment of the invention, a patient, such as a patient's eye, is determined to be at risk of disease. This may be performed before an imaging anomaly is detectable. Such a determination may be made by ascertaining whether the patient is at risk for a chronic progressive disease, such as retinopathy, including diabetes, age-related macular degeneration, or retinitis pigmentosa. Alternatively or additionally, the results of the patient's examination or test may be abnormal. Specific tests, such as physiological tests or genetic tests, may be performed to confirm that the patient is at risk for disease.

When treating or prophylactically protecting a retina or other eye tissue having or at risk of a chronic progressive disease, a laser beam is generated that is sub-lethal and creates a true sub-threshold photocoagulation in the retina tissue, and at least a portion of the retina tissue is exposed to the generated laser beam without damaging the exposed retina or foveal tissue, thereby providing a prophylactic and protective treatment of the retina tissue of the eye. The retina being treated may include the fovea, Retinal Pigment Epithelium (RPE), choroid, choroidal neovascular membrane, subretinal fluid collection, macula, macular edema, parafovea, and/or perifoveal area. The laser beam may be directed to only a portion of the retina, or substantially the entire retina and fovea.

Although most therapeutic effects appear to be long-term (if not permanent), clinical observations suggest that it appears to occasionally disappear. Accordingly, the tissue is periodically retreated. This may be performed on an established schedule or when it is determined that the patient's tissue needs to be retreated, for example by periodically monitoring the patient's visual and/or retinal function or condition.

Although the invention is particularly suitable for the 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 the method can take trabecular meshwork (trabecular mesh) as a target for treating glaucoma, and are realized by another customized treatment field template. Moreover, treatment of retinal tissue with SDM in eyes with progressive open angle glaucoma (as described above) has shown key indicators of improvement in optic nerve and ganglion cell function, indicating a significant neuroprotective effect of this treatment. The visual field is also improved without adverse therapeutic effects. Thus, it is believed that SDMs according to the present invention can assist in the clinical management of glaucoma by reducing the risk of vision loss independent of intraocular pressure (IOP) reduction.

As detailed above, low intensity/high density sub-threshold (sub-lethal) diode micro-pulsed lasers (SDMs) have proven effective in treating traditional retinal laser indications such as diabetic macular edema, proliferative diabetic retinopathy, central serous chorioretinopathy, and retinal branch vein occlusion without adverse therapeutic effects. As mentioned above, the mechanism of retinal laser therapy is sometimes referred to herein as the "reset to default" theory, which assumes that the primary mode of retinal laser action is the sub-lethal activation of the Retinal Pigment Epithelium (RPE) heat shock proteins.

Recent studies performed by the inventors have also shown that SDM should be neuroprotective in open angle glaucoma. Linear regression analysis showed that the most abnormal values before treatment improved the most after treatment for almost all measures. In accordance with the present invention, a key index for the improvement of optic nerve and ganglion cell function in the treatment of total macular SDM in eyes with advanced open-angle glaucoma (OAG) indicates a significant neuroprotective effective treatment. The visual field is also improved without adverse therapeutic effects. Thus, generating a micro-pulsed laser beam having the above characteristics and parameters and applying the laser beam to the retina and/or foveal tissue of an eye suffering from or at risk of glaucoma produces a therapeutic effect on the retina and/or foveal tissue exposed to the laser beam without damaging or permanently damaging the retina and/or foveal tissue and also improves the function or condition of the optic nerve and/or retinal ganglion cells of the eye.

Retinal ganglion cells and the optic nerve are affected by the health and function of the Retinal Pigment Epithelium (RPE). Retinal homeostasis is maintained by RPE primarily via the still poorly understood but extremely complex interaction of small proteins secreted by RPE into the intercellular space, called "cytokines". Some RPE-derived cytokines such as pigment epithelium-derived factor (PEDF) are neuroprotective. Retinal laser treatment can alter RPE cytokine expression, including but not limited to increasing expression of PEDF. In accordance with the present invention, SDM acts as a "syntrophic" to normalize retinal function in the absence of retinal damage. By normalizing RPE function, retinal autoregulation and cytokine expression are thus also normalized. This suggests that normalization of retinal cytokine expression may be the source of the neuroprotective effects of SDM in OAG.

Although SDM has a significant beneficial effect on chronic progressive retinal disease, most of these diseases have no other treatments with any benefit. In this regard, retinal CPD also resembles CPD elsewhere. In all CPDs including type II diabetes, alzheimer's disease, Idiopathic Pulmonary Fibrosis (IPF) and ischemic heart disease, as well as various cardiomyopathies, it is beneficial to have identified abnormalities in the HSP system and to find stimulation. Currently, outside of the present invention, there is no non-physical therapy to stimulate HSP syntropy in systemic CPD. Experience with SDM associated with eye disease has shown that a properly designed PEMR should effectively and safely treat any CPD affecting any other part of the body. Moreover, experience with SDM in otherwise untreatable retinal diseases has shown that the beneficial effects of PEMR elsewhere should be important rather than trivial, robust, significant, and safe. Like SDM, the effect of PEMRs on CPD elsewhere in the body will most likely not cure the primary cause of the disease (age, diabetes, genetic defects, etc.), but instead will slow, arrest or reverse the disease process by repairing abnormalities that develop as a result of the primary disease defect. Maintaining therapeutic benefit through regular retreatment, the course of the disease process should be attenuated, thereby reducing the risk of death and disability.

Since heat shock proteins play a role in responding to a number of abnormal conditions in body tissues other than ocular tissues, it is believed that similar systems and methods may be advantageously used to treat such abnormal conditions, infections, etc. Therefore, the present invention also relates to the controlled application of pulsed ultrasound or electromagnetic radiation to treat abnormal conditions, including inflammation, autoimmune conditions, and cancer accessible through fiber optics and focused electromagnetic/acoustic waves of an endoscope or surface probe. For example, cancer on the surface of the prostate with the greatest threat of metastasis is accessible through fiber optics in a proctoscope. Colonic tumors can be accessed by fiber optic systems, such as those used in colonoscopy.

As shown above, sub-threshold diode pulsed laser (SDM) light stimulation is effective in stimulating the direct repair of slightly misfolded proteins in ocular tissues. Another route that may occur in addition to HSP activation is because the temperature spike caused by the micropulse in the form of a thermal time-course allows water to diffuse inside the protein, and this allows the cleavage of peptide-peptide hydrogen bonds that prevent the protein from returning to its native state. Diffusion of water into proteins results in an increase in the number of inhibitory hydrogen bonds of the order of a thousand fold. Thus, it is believed that this process may also be advantageously applied to other diseases.

Laser treatment can induce HSP production or activation and alter cytokine expression. The more sudden and severe the non-lethal cellular stress (e.g., laser radiation), the faster and robust the HSP activation. Thus, the bursts of repetitive low temperature thermal peaks with very high rates of change (rise of about 7 ℃, or 70,000 ℃/sec per 100 microsecond micropulse) generated by each SDM irradiation are particularly effective in stimulating the activation of HSPs, especially compared to non-lethal irradiation with sub-threshold treatment with continuous wave lasers (which can replicate only low average tissue temperature rise).

In accordance with the system and method of the present invention, a pulsed energy source, such as a laser, ultrasound, ultraviolet light, radiofrequency, microwave radiofrequency, or the like, has an energy parameter selected to induce a thermal time course in the tissue or body fluid to raise the target tissue or body fluid temperature to a sufficient level during a short period of time to achieve a therapeutic effect while maintaining the average tissue temperature below a predetermined level during a long period of time to avoid permanent tissue damage. It is believed that the creation of this thermal time course stimulates heat shock protein activation or production and promotes 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 are important to create the thermal time-course to achieve a therapeutic effect without causing damage.

The choice of these parameters can be determined by requiring an Arrhenius integral greater than 1 or one for HSP activation. Arrhenius integration was used to analyze the effect on biological tissue. See, for example, The CRC handbook Thermal Engineering, Frank Kreith, ed, Springer Science and dBusiness Media (2000). At the same time, the selected parameters must not permanently damage the tissue. Therefore, Arrhenius integrals for lesions can also be used, wherein the solved Arrhenius integral is smaller than 1 or one.

Alternatively, FDA/FCC limits in terms of energy deposition and temperature rise per unit gram of tissue measured over a period of several minutes are met to avoid permanent tissue damage. FDA/FCC requirements for energy deposition and temperature rise are widely used and can be referenced, for example, in www.fda.gov/media/resolution and regulation/regulation documents/ucm073817.htm # attacha for electromagnetic sources, and astrosio and p.larivero, edited emitting Imaging Technologies (Emerging Imaging technology). CRC Press (2012), for ultrasonic sources.

Generally, a tissue temperature rise between 6 ℃ and 11 ℃ over a short period of time (e.g., seconds or fractions of a second) can produce a therapeutic effect, e.g., by activating heat shock proteins, but keeping the average tissue temperature below a predetermined temperature (e.g., 6 ℃ and even 1 ℃ or less in certain circumstances) over a long period of time (e.g., over a period of minutes (e.g., 6 minutes)) will not permanently damage the tissue.

As noted above, the energy source to be applied to the target tissue will have energy and operating parameters that must be determined and selected to achieve a therapeutic effect without permanently damaging the tissue. For example, in the case of using a beam energy source, such as a laser beam, the laser wavelength, duty cycle, and total pulse train duration parameters must be considered. Other parameters that may be considered include the radius of the laser source and the average laser power. Adjusting or selecting one of these parameters may affect at least one other parameter.

Fig. 10 and 11 show graphs of the average power in watts compared to the laser source radius (between 0.1cm and 0.4 cm) and the pulse train duration (between 0.1 and 0.6 seconds). Fig. 10 shows a wavelength of 880 nanometers, while fig. 11 has a wavelength of 1000 nanometers. It can be seen that in these figures, the required power decreases monotonically with decreasing source radius, with increasing total column duration, and with decreasing wavelength. The preferred parameter for the radius of the laser source is 1 mm to 4 mm. For a wavelength of 880 nanometers, the minimum power value is 0.55 watts with a laser source radius of 1 millimeter and a total pulse duration of 600 milliseconds. The maximum power value for a wavelength of 880 nanometers is 52.6 watts when the laser source radius is 4 millimeters and the total pulse train duration is 100 milliseconds. However, when a laser having a wavelength of 1000 nm is selected, the minimum power value is 0.77 watts with a laser source radius of 1 mm and a total pulse train duration of 600 msec, and the maximum power value is 73.6 watts when the laser source radius is 4 mm and the total pulse train duration is 100 msec. The corresponding peak power during a single pulse is obtained by dividing the average power by the duty cycle.

The volume of the tissue region to be heated is determined by the wavelength, the absorption length in the relevant tissue, and the beam width. The total pulse duration and average laser power determine the total energy delivered to heat the tissue, and the duty cycle of the pulse train gives the peak value of the correlation, or the peak power of the correlation with the average laser power. Preferably, the energy parameters of the pulsed energy source are selected to absorb between about 20 and 40 joules per cubic centimeter of target tissue.

In the thin melanin layer in the retinal pigment epithelium, the absorption length is very small. In other parts of the body, the absorption length is usually not so small. The penetration depth and skin is in the range of 0.5 mm to 3.5 mm in wavelengths ranging from 400 nm to 2000 nm. The penetration depth into human mucus tissue is in the range of 0.5 mm to 6.8 mm. Accordingly, the heating volume will be limited to providing an outer or inner surface of the radiation source, the depth being equal to the penetration depth, and the lateral dimension being equal to the lateral dimension of the radiation source. Since diseased tissue near the outer surface or near the inner accessible surface is treated using a beam energy source, a source radius of between 1 mm and 4 mm and operating at a wavelength of 880 nm produces a penetration depth of about 2.5 mm and a wavelength of 1000 nm produces a penetration depth of about 3.5 mm.

It has been determined that the target tissue can be heated up to about 11 ℃ for a short period of time, e.g., less than 1 second, to produce the therapeutic effect of the present invention, while maintaining the average temperature of the target tissue in a lower temperature range, e.g., less than 6 ℃ or even 1 ℃ or less, for a long period of time, e.g., several minutes. The selection of the duty cycle and the total pulse train duration provides a time interval over which heat can be dissipated. It has been found that a duty cycle of less than 10% and preferably between 2.5% and 5% is effective with a total pulse duration between 100 and 600 milliseconds. Fig. 12 and 13 show the time for a laser source having a radius between 0.1 and 0.4 centimeters to decay from 10 ℃ to 1 ℃ for the case of fig. 12 at a wavelength of 880 nanometers and in fig. 13 at a wavelength of 1000 nanometers. It can be seen that when using a wavelength of 880 nanometers, the decay time is short, but both wavelengths are within acceptable requirements and operating parameters to obtain the benefits of the present invention without causing permanent tissue damage.

It has been found that an increase in the average temperature rise of the desired target area of at least 6 ℃ and up to 11 ℃, and preferably about 10 ℃, during total irradiation results in HSP activation. Control of target tissue temperature is determined by selecting source and target parameters such that Arrhenius score for HSP activation is greater than 1 while ensuring compliance with conservative FDA/FCC requirements to avoid injury or damage Arrhenius score less than 1.

To meet conservative FDA/FCC limits to avoid permanent tissue damage, the average temperature rise of the target tissue during any 6 minutes is 1 ℃ or less for the beam and other electromagnetic radiation sources. The typical decay time required for the temperature of the heated target region to decrease from a temperature rise of about 10 c to 1c by thermal diffusion is shown in the above fig. 12 and, as can be seen from fig. 12, the temperature decay time is 16 seconds when the wavelength is 880 nanometers and the source diameter is 1 millimeter. The temperature decay time was 107 seconds when the source diameter was 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. This is well within the time to maintain the average temperature rise over the course of several minutes (e.g., 6 minutes or less). Although the temperature of the target tissue is raised, for example, to about 10 ℃ very quickly (e.g., within a fraction of a second) during application of the energy source to the tissue, the lower duty cycle provides a longer period of time between energy pulses applied to the tissue and the shorter pulse train duration ensures sufficient temperature diffusion and decay over a shorter period of time including minutes (e.g., 6 minutes or less) so that there is no permanent tissue damage.

The parameters of each energy source (including microwave, infrared laser, radio frequency, and ultrasound) are different because the absorption properties of tissue are different for these different types of energy sources. Tissue water content can vary with tissue type, however, under normal or near normal conditions, consistency in tissue properties can be observed, allowing for disclosure of tissue parameters, which are widely used by clinicians to design treatments. The following is a table showing the properties of electromagnetic waves in bio media, table 1 relates to muscles, skin and tissues having high water content, and table 2 relates to fats, bones and tissues having low water content.

Table 1 properties of electromagnetic waves in bio-media: muscle, skin and tissue with high water content

Table 2 properties of electromagnetic waves in bio-media: fat, bone and tissue with low water content

The absorption length of radio frequency in body tissue is long compared to body size. Thus, the heating zone is determined by the size of the coil as the source of the radio frequency energy, rather than by the absorption length. At a long distance r from the coil, the (near) magnetic field of the coil is 1/r³The speed of (3) decreases. At smaller distances, the electric and magnetic fields can be represented by vector magnetic potentials which can be represented in closed form by elliptical integrals of the first and second classes, respectively. Heating only occurs in areas comparable in size to the size of the coil source itself. Accordingly, if it is desired to preferentially heat a region characterized by a radius, the source coil will be selected to have a similar radius. Due to 1/r of the magnetic field³The drop, outside the hemispherical region of the radius, is rapid with heating. Since it is recommended to use a radio frequency that can only access diseased tissue from the outside or from the lumen, it is reasonable to consider a coil radius of between about 2 and 6 millimeters.

The radius of the source coil and the number of ampere-turns in the source coil give the magnitude and spatial extent of the magnetic field, and the radio frequency is a factor that relates the magnitude of the electric field to the magnitude of the magnetic field. Heating is proportional to the product of the electrical conductivity and the square of the electric field. For target tissues of interest near the outer or inner surface, the electrical conductivity is that of skin and mucous tissues. The duty cycle of the pulse train and the total train duration of the pulse train are factors that affect how much total energy is delivered to the tissue.

Preferred parameters of the radio frequency energy source have been determined as a coil radius between 2 and 6 mm, a radio frequency in the range of 3 to 6MHz, a total pulse train duration of 0.2 to 0.4 seconds, and a duty cycle between 2.5% and 5%. Figures 14 to 17 show how the number of ampere turns varies with these parameters to give a temperature rise that produces an Arrhenius integral of about 1 or one for HSP activation. Referring to fig. 14, for an RF frequency of 6MHz, a pulse train duration between 0.2 and 0.4 seconds, a coil radius between 0.2 and 0.6 centimeters, and a 5% duty cycle, the peak ampere-turns (NI) is 13 at a coil radius of 0.6 centimeters and 20 at a coil radius of 0.2 centimeters. For a 3MHz frequency, as shown in fig. 15, the peak ampere-turns is 26 when the pulse train duration is 0.4 seconds and the coil radius is 0.6 centimeters and the duty cycle is 5%. However, for the same 5% duty cycle, the peak ampere-turns is 40 when the coil radius is 0.2 centimeters and the pulse train duration is 0.2 seconds. In fig. 16 and 17, a duty ratio of 2.5% is used. As shown in fig. 16, 18 ampere turns were generated for a 6MHz radio frequency with a coil radius of 0.6 cm and a pulse train duration of 0.4 seconds, and 29 ampere turns were generated when the coil radius was only 0.2 cm and the pulse train duration was 0.2 seconds. Referring to fig. 17, with a 2.5% duty cycle and a radio frequency of 3MHz, the peak ampere-turns is 36 when the pulse train duration is 0.4 seconds and the coil radius is 0.6 centimeters, and 57 ampere-turns when the pulse train duration is 0.2 seconds and the coil radius is 0.2 centimeters.

Fig. 18 shows the time (in seconds) for the decay of the temperature rise from about 10 ℃ to about 1 ℃ for a coil radius between 0.2 cm and 0.6 cm for a radio frequency energy source. The temperature decay time was about 37 seconds when the radio frequency coil radius was 0.2 cm, and about 233 seconds when the radio frequency coil radius was 0.5 cm. When the radio frequency coil radius is 0.6 centimeters, the decay time is about 336 seconds, which is still within the acceptable decay time range, but at the upper end of the range.

Microwaves are another type of electromagnetic energy source that may be used in accordance with the present invention. The frequency of the microwaves determines the tissue penetration distance. The gain of a conical microwave horn is greater than the microwave wavelength, indicating that in these cases the energy is mainly radiated in a narrow forward load. Typically, the microwave source used in accordance with the present invention has a linear dimension on the order of centimeters or less, so that 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 the internal body cavity and can also be used to irradiate the external surface. In this case, the heating zone may be approximated as a hemisphere with a radius equal to the absorption length of the microwaves in the body tissue to be treated. When microwaves are used to treat tissue near the outer surface or a surface accessible from the lumen, frequencies in the range of 10 to 20GHz are used, with corresponding penetration distances of only between about 2 and 4 millimeters.

The temperature rise of the tissue using a microwave energy source is determined by the average power of the microwaves and the total pulse train duration. The duty cycle of the pulse train determines the peak power of the individual pulses in the pulse train. Pulse train durations of 0.2 and 0.6 seconds are preferred when a radius of the source of less than about 1cm is employed, and frequencies between 10 and 20GHz are typically used.

The required power decreases monotonically with increasing column duration and with increasing microwave frequency. For a frequency of 10GHz, the average power was 18 watts when the pulse train duration was 0.6 seconds, and 52 watts when the pulse train duration was 0.2 seconds. For a 20GHz microwave frequency, an average power of 8 watts was used when the pulse train was 0.6 seconds, and the average power could be 26 watts when the pulse train duration was only 0.2 seconds. The corresponding peak power is simply obtained by dividing the average power by the duty cycle.

Referring now to FIG. 19, a graph is shown of the average microwave power (in watts) for microwaves having a frequency of 10GHz and a pulse train duration between 0.2 seconds and 0.6 seconds. Fig. 20 is a similar graph but shows the average microwave power for microwaves having a frequency of 20 GHz. It will thus be seen that the average microwave source power varies with the total column duration and with the microwave frequency. However, the control conditions were that the Arrhenius integral for HSP activation in the heating zone was about 1.

Referring to FIG. 21, a graph is shown of the time (in seconds) for the temperature to decay from about 10 ℃ to 1 ℃ compared to the microwave frequency between 58MHz and 20000 MHz. The minimum and maximum temperature decay for the preferred microwave frequency range is 8 seconds for a microwave frequency of 20GHz and 16 seconds for a microwave frequency of 10 GHz.

The use of ultrasound as an energy source can heat surface tissue, as well as tissue having different depths in the body, including relatively deep tissue. The absorption length of ultrasound in the body is quite long, as it is demonstrated by the widespread use for imaging. Accordingly, the ultrasound can be focused at a target region deep within the body, with the heating of the focused ultrasound beam being primarily focused at the approximately cylindrical focal region of the beam. The volume of the heating zone is determined by the length of the focal waist of the airy disc (airy disc) and the focal waist region, i.e. the confocal parameter. Multiple beams from sources at different angles may also be used, with heating occurring at overlapping focal regions.

For ultrasound, the relevant parameters for determining tissue temperature are the frequency of the ultrasound, the total column duration, and the transducer power, given the focal length and diameter of the ultrasound transducer. The frequency, focal length, and diameter determine the volume of the focal zone where the ultrasound energy is concentrated. The focal volume includes a target volume of tissue to be treated. Transducers having a diameter of about 5 cm and a focal length of about 10 cm are readily available. A favorable focal spot size is obtained when the ultrasound frequency is between 1 and 5MHz and the total column duration is 0.1 to 0.5 seconds. For example, for a focal length of 10 centimeters and a transducer diameter of 5 centimeters, the focal volume is 0.02 cubic centimeters at 5MHz and 2.36 cubic centimeters at 1 MHz.

Referring now to fig. 22, a graph is shown of average source power (in watts) versus frequency (between 1MHz and 5 MHz) and pulse train duration (between 0.1 and 0.5 seconds). Assuming a transducer focal length of 10 cm and a source diameter of 5 cm. The power required to give an Arrhenius integral for HSP activation of about 1 decreases monotonically with increasing frequency and with increasing total column duration. Given the preferred parameters, the minimum power is 5.72 watts for a 1GHz frequency and a pulse train duration of 0.5 seconds, while the maximum power is 28.6 watts for a 1GHz frequency and a pulse train duration of 0.1 seconds. For a 5GHz frequency, 0.046 watts is required for a pulse train duration of 0.5 seconds, wherein 0.23 watts is required for a pulse train duration of 0.1 seconds. The corresponding peak power during a single pulse is simply obtained by dividing by the duty cycle.

Figure 23 shows the time (in seconds) for the temperature to diffuse or decay from 10 ℃ to 6 ℃ when the ultrasound frequency is between 1 and 5 MHz. Figure 24 shows the time (in seconds) to decay from about 10 ℃ to 1 ℃ for ultrasound frequencies from 1 to 5 MHz. For a preferred focal length of 10 cm and a transducer diameter of 5 cm, the maximum temperature decay time is 366 seconds when the ultrasound frequency is 1MHz and the minimum temperature decay is 15 seconds when the microwave frequency is 5 MHz. For a test time of several minutes, a decay time of 366 seconds at 1MHz to reach a temperature rise of 1 ℃ during several minutes is permissible when the FDA requires only a temperature rise of less than 6 ℃. As can be seen from fig. 23 and 24, the decay time of the temperature rise at 6 ℃ is about 70 times smaller than the temperature rise at 1 ℃.

Figure 25 shows the volume (in cubic centimeters) of the focal heating zone compared to the ultrasound frequency between 1 and 5 MHz. Considering ultrasound frequencies between 1 and 5MHz, the respective focal spot sizes for these frequencies range from 3.7 mm to 0.6 mm, and the length of the focal zone ranges from 5.6 cm to 1.2 cm. The corresponding treatment volume ranges between about 2.4 cubic centimeters and 0.02 cubic centimeters.

An example of a parameter that gives a desired HSP activation Arrhenius integral greater than 1 and an impairment Arrhenius integral less than 1 is a total ultrasound power between 5.8 and 17 watts, a pulse duration of 0.5 seconds, an interval between pulses of 5 seconds, with a total number of pulses 10 over a total pulse flow time of 50 seconds. The target treatment volume will be about 1 mm on a side. By applying multiple ultrasound in multiple simultaneously applied adjacent but spaced-apart columns, a large treatment volume can be treated with an ultrasound system like a laser diffractive optical system. The multiple focused ultrasound beams converge on a very small therapeutic target within the body, which convergence allows for minimal heating, except for overlapping beams at the target. This region will be heated and stimulate HSP activation and promote protein repair by transient hyperthermic spikes. However, given the pulse aspect of the present invention and the smaller area treated at any given time, the treatment meets the FDA/FCC requirement of a long-term (minutes) average temperature rise <1 k. An important difference between the present invention and existing therapeutic heat treatments for pain and muscle strain is that there are no high T peaks in the prior art that are required for efficient HSP activation and promotion of protein repair to provide a cure at the cellular level.

The pulse train energy delivery pattern has distinct advantages over either a single pulse or a progressive energy delivery pattern in terms of remedial HSP activation and promotion of protein repair. There are two considerations that make this advantageous:

first, one major advantage of HSP activation and protein repair in the PEMR energy delivery mode comes from the generation of peak temperatures on the order of 10 ℃. Such a large temperature rise has a large impact on the Arrhenius score, which quantifies the number of activated HSPs and the rate of diffusion of water into the protein that promotes protein repair. This is because the temperature constitutes an index having an amplifying effect.

It is important that the temperature rise does not remain high (10 ℃ or higher) for a long time, since then the FDA and FCC requirements that the average temperature rise must be less than 1 ℃ (or 6 ° in the case of ultrasound) over a period of minutes are violated.

SDM or other PEMR energy delivery modes uniquely satisfy both of these considerations by judicious selection of power, pulse time, pulse spacing, and volume of the target region to be treated. The volumetric inclusion of the treatment zone is due to the fact that the temperature must decay fairly quickly from its high value, on the order of 10 c, so that the long-term average temperature rise does not exceed the long-term FDA/FCC limit (6 c for ultrasound frequencies and 1c or less for electromagnetic radiation energy sources).

For a region having a linear dimension L, the time it takes for the peak temperature to decay e-fold in the tissue is about L²/16D, wherein D is 0.00143cm²The typical thermal diffusivity is in seconds. For example, if L is 1 mm, the decay time is about 0.4 seconds. Accordingly, for a1 mm area on one side, a train of 10 pulses, each of 0.5 seconds duration, with 5 seconds between pulses, can achieve the desired instantaneous high temperature rise while still not exceeding the average long-term temperature rise of 1 ℃. This is further demonstrated below.

The limitation of the heating volume is the reason that RF electromagnetic radiation is not as good an option for treating deep regions of the body as ultrasound. Long skin depths (penetration distances) and ohmic heating along the skin depth result in large heating volumes whose thermal inertia does not allow for reaching high peak temperatures to activate HSPs and promote protein repair, nor does it allow for rapid temperature decay to meet the long-term FDA and FCC limits of average temperature rise.

Ultrasound has been used to therapeutically heat areas of the body to relieve pain and muscle strain. However, this heating does not follow the protocol of the present invention and does not have a temperature peak responsible for the excitation of the HSP.

Next, a set of focused ultrasound beams is considered, which are directed at a target region deep within the body. To simplify the mathematics, it is assumed that the beams are replaced by a single source with a spherical surface shape focused on the center of the sphere. The absorption length of the ultrasound can be quite long. Table 3 below shows typical absorption coefficients for ultrasound at 1 MHz. The absorption coefficient is roughly proportional to the frequency.

TABLE 3 typical absorption coefficient of 1MHz ultrasound in body tissue

Assuming that the geometric changes in the incident radiation due to focusing dominate any changes due to attenuation, the intensity of the incident ultrasound at a distance r from the focal point can be approximately written as:

I(r)＝P/(4πr²) (1)

where P represents the total ultrasound power.

Short pulse duration t at r_pThe temperature rise at the end is

dT(t_p)＝Pαt_p/(4πC_vr²) (2)

Wherein α is the absorption coefficient and C_vThe heat capacity is constant. This continues until r is reached, at which point t_pBecomes comparable to r or reaches the diffraction limit of the focused beam. For smaller r, the temperature rise is substantially independent of r. For example, assume that the diffraction limit is reached at a small radial distance compared to the radial distance determined by thermal diffusion. Then

r_dif＝(4Dt_p)^1/2(3)

Wherein D is the thermal diffusivity, and for r<r_difAt t_pHas a temperature rise of

dT(r_dif,t_p)＝3Pα/(8πC_vD) Wherein r is<r_dif(4)

Thus, at the end of the pulse, we can write for a temperature rise:

dT_p(r)＝{Pαt_p/(4πC_v}[(6/r_dif ²)U{r_dif-r)+(1/r²)U(r-r_dif)](5)

applying Green (Green) function for thermal diffusion

G(r,t)＝(4ΩDt)^-3/2exp[-r²/(4Dt)](6)

For this initial temperature profile, we find that the temperature dt (t) at which the focal point r is 0 at time t is

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_vD) (8)

The following equation provides a good approximation of equation (7):

dT(t)≈dT_o(t_p/t)^3/2(9)

as can be seen in FIG. 26, this figure is for dT (t)/dT at the target treatment area_oComparison of the formulae (7) and (9). The bottom curve is an approximate representation of equation (9).

The Arrhenius integral for the N pulse trains can now be evaluated by the temperature rise given by equation (9). In the formula (I), the reaction mixture is,

dT_N(t)＝∑dT(t-nt_I) (11)

wherein, dT (t-nt)_I) Is represented by the formula (9), t is represented by t-nt_IReplacement and t_IRepresenting the interval between pulses.

The Arrhenius integral can be approximately evaluated by dividing the integration interval into a portion where a temperature peak occurs and a portion where a temperature peak does not exist. The sum of the contributions at the temperature peaks can be simplified by applying the end-point formula of Laplace (Laplace) as an integral over the temperature peaks. Furthermore, the integration over the part where the peak is not present can be simplified by noting that the non-peak temperature rise reaches the asymptotic value very quickly, so that a good approximation is obtained by replacing the change time rise with the asymptotic value. When these approximations are performed, equation (10) becomes:

Ω＝AN[{t_p(2k_BT_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)

wherein,

dT_N(Nt_I)≈2.5dT_o(t_p/t_I)^3/2(13)

(2.5 in formula (13) is generated from (N-N)^-3/2And is the magnitude of the harmonic number (N,3/2) for typical interest N)

It is interesting to compare this equation with the equation for SDM applied to the retina. The first term is very similar to that of the peak contribution in the retinal case, except that the effective peak separation is reduced by a factor of 3 for this three-dimensional convergent beam case. Comprising dT_N(Nt_I) Is much smaller than in the case of the retina. The background temperature rise is comparable in magnitude to the peak temperature rise. However, here, in the case of a converging light beam, the background temperature rise is small (t)_p/t_I)^3/2The ratio of (a) to (b). This points to the importance of the peak contribution to the activation or production of HSPs and promotion of protein repair, since the background temperature rise, similar to that in the case of continuous ultrasound heating, is insignificant compared to the peak contribution. At the end of the pulse train, even this low background temperature rise quickly disappears by thermal diffusion.

FIGS. 27 and 28 show the pulse duration t_p0.5 second, pulse interval t_I10 seconds and total number of pulses N10, the magnitude of the logarithm of the Arrhenius integral for injury and for HSP activation or production is plotted against dT_oAnd changes accordingly. For pulse duration t_p0.5 second, pulse interval t_I10 seconds and the total number of ultrasound pulses N10, the logarithm of the Arrhenius integral (equation 12) for lesions and for HSP activation is a function of the temperature rise dT from the individual pulses_o(in degrees kelvin) changes. FIG. 27 shows the Arrhenius constant A ═ 8.71x10³³sec^-1And E ═ 3.55x10^-12Logarithm of damage integral for ergs. Fig. 28 shows Arrhenius constant a ═ 1.24x10²⁷sec^-1And E2.66 x10^-12Log of HSP activation score for ergs. Graphical displays in FIGS. 27 and 28Is shown at up to dT_oOver 11.3k, omega_damageIs more than 1 and omega_hspGreater than 1 over the entire interval shown, which is the condition required for cell repair without damage.

Formula (8) shows that when α ═ 0.1cm^-1This is easily achieved by obtaining a dto of 11.5K with a total ultrasonic power of 5.8 watts if α is increased by a factor of 2 or 3, the resulting power is still easily achieved_d＝(4Dt_p)^1/2Volume) of 0.00064 cubic centimeters. This corresponds to a 0.86 mm cube on one side.

This simple example demonstrates that focused ultrasound should be available to stimulate reparative HSPs deep in the body by readily available equipment.

To expedite treatment of larger internal volumes, the SAPRA system may be used.

The pulsed energy source may be directed to the exterior of the body adjacent to a target tissue or having a blood supply proximate to a surface of the exterior of the body. Alternatively, a device can be inserted into a body lumen to apply a pulsed energy source to a target tissue. Whether the energy source is applied to the exterior of the body or the interior of the body and what type of device is used depends on the energy source selected and used to treat the target tissue.

Light stimuli in accordance with the present invention can be efficiently delivered to internal surface regions or tissues of the body through the use of an endoscope (e.g., bronchoscope, proctoscope, colonoscope, etc.). Various endoscopes consist essentially of a flexible tube which itself contains one or more internal tubes. Typically, one of the inner tubes includes a light pipe or multimode optical fiber that guides light along the endoscope to illuminate the region of interest and enable the physician to see objects at the illuminated end. The other inner tube may consist of a wire that delivers current to enable the surgeon to cauterize the irradiated tissue. Yet another inner tube may consist of a biopsy tool that enables the physician to cut and retain any irradiated tissue.

In the present invention, one of these inner tubes is used as an electromagnetic radiation tube, such as a multimode fiber, to transmit an SDM or other electromagnetic radiation pulse, which is fed into the endoscope at the end held by the physician. Referring now to FIG. 29, a light generation unit 10 (e.g., a laser having a desired wavelength and/or frequency) is used to generate electromagnetic radiation, such as laser light, in a controlled, pulsed manner that is delivered through a light pipe 52 to the distal end of an endoscope 54 (shown in FIG. 30) that is inserted into the body and the laser or other radiation 56 is delivered to the target tissue 58 to be treated.

The light generating unit 10 of fig. 29 may comprise a light generating unit as described above with reference to fig. 1 to 6. However, the delivery device or assembly may include an endoscope, bronchoscope, and pass the generated laser beam through light pipe 52. The system may comprise a laser beam projector or delivery device such as an endoscope, and the viewing system/camera will comprise two distinct components when in use. The viewing system/camera may provide feedback to a display monitor, which may also include the necessary computerized hardware, data input and control to operate the optics, delivered laser or other pulsed energy source, and/or projection/viewing components. Also, a pattern that can be shifted can be generated, as described above. Of course, the laser generation system of fig. 1-6 is exemplary, and other devices and systems may be used to generate laser light or other pulsed electromagnetic radiation sources that may be operatively passed through a projector device, such as the endoscope or light pipe shown in fig. 29 and 30.

Other forms of electromagnetic radiation may also be generated and used, including ultraviolet waves, microwaves, other radio frequency waves, and lasers at predetermined wavelengths. Moreover, ultrasound can also be generated and used to create a thermal time course temperature peak in the target tissue sufficient to activate or produce heat shock proteins in cells of the target tissue without damaging the target tissue itself. To this end, a source of pulsed ultrasonic or electromagnetic radiation energy is typically provided and applied to the target tissue by momentarily elevating the temperature of the target tissue (e.g., between 6 ℃ and 11 ℃) while only 6 ℃ or 1 ℃ or less is maintained for a prolonged period (e.g., during minutes).

For deep tissues that are not near the internal aperture, light pipes are not an effective way to deliver pulse energy. In this case, pulsed low frequency electromagnetic energy or preferably pulsed ultrasound may be used to induce a series of temperature peaks in the target tissue.

Thus, in accordance with the present invention, a source of pulsed ultrasound or electromagnetic radiation is applied to a target tissue or fluid to stimulate HSP production or activation and promote protein repair in living animal tissue. In general, the electromagnetic radiation may be ultraviolet waves, microwaves, other radio frequency waves, laser light at a predetermined wavelength, and the like. On the other hand, if electromagnetic energy is to be used for deep tissue targets that are far from the natural aperture, the absorption length limits the wavelength to that of microwave or radio frequency waves, depending on the depth of the target tissue. However, for deep tissue targets far from the natural orifice, relatively long wavelength electromagnetic radiation, preferably ultrasound, is preferred.

Ultrasound or electromagnetic radiation is pulsed to create a thermal time course in the tissue that stimulates HSP production or activation and promotes protein repair without causing damage to the cells and tissues being treated. The area and/or volume of the tissue being treated is also controlled and minimized to peak temperatures on the order of several degrees, e.g., about 10 ℃, while maintaining a long-term temperature rise less than the FDA specified limit, e.g., 1 ℃. It has been found that if too large a tissue area or volume is treated, the increased temperature of the tissue does not diffuse sufficiently rapidly to meet FDA requirements. However, limiting the area and/or volume of the tissue being treated and creating a source of pulsed energy achieves the goals of the present invention of stimulating HSP activation or production by heating or otherwise stressing cells and tissues, while allowing the treated cells and tissues to dissipate any excess heat generated to within acceptable limits.

Stimulation of HSP production in accordance with the present invention is believed to be effective in treating a variety of tissue abnormalities, conditions, and even infections. For example, viruses that cause colds primarily affect the small orifices 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. 31, a cross-sectional view of a human head 60 is shown with endoscope 54 inserted into nasal cavity 62 and energy 56, such as a laser or the like, directed to tissue 58 within nasal cavity 62 to be treated. Tissue 58 to be treated may be located within nasal cavity 62, including the nasal passages, as well as the nasopharynx.

To ensure absorption of the laser energy or other energy source, the wavelength can be tuned to the Infrared (IR) absorption peak of water, or an adjuvant dye can be used to act as a photosensitizer. In this case, the treatment will then consist of the following procedure: the adjuvant is drunk or topically applied, waiting a few minutes for the adjuvant to penetrate the surface tissue, and then providing a laser or other energy source 56 to the target tissue 58 for a few seconds, e.g., through an optical fiber in the endoscope 54, as shown in fig. 31. For patient comfort, the endoscope 54 may be inserted after the local anesthetic is applied. If necessary, the process may be repeated periodically, for example, for about a day.

The treatment will stimulate the activation or production of heat shock proteins and promote protein repair without damaging the cells and tissues being treated. As mentioned above, specific heat shock proteins have been found to play an important role in the immune response and the health of target cells and tissues. The energy source may be a monochromatic laser source, such as a 810 nanometer wavelength laser, provided in a manner similar to that described in the above-mentioned patent application, but provided through an endoscope or the like, as shown in fig. 31. The adjuvant dye is selected to increase laser light absorption. While this includes certain preferred methods and embodiments for carrying out the invention, it should be understood that other types of energy and delivery means may be used to achieve the same objectives in accordance with the present invention.

Referring now to fig. 32, a similar situation exists for other diseases, where the primary target is the epithelium of the upper respiratory tree, in a section greater than about 3.3 millimeters in diameter, i.e., the upper six generations of the upper respiratory tree. The thin mucus layer separates the target epithelial cells from the airway lumen, i.e., the layer in which antigen-antibody interactions occur, resulting in inactivation of viruses such as the cold and influenza viruses.

With continued reference to fig. 32, flexible light tube 52 of bronchoscope 54 is inserted through the individual's mouth 64, through the throat and trachea 66, and into the bronchi 68 of the respiratory tree. Here, a laser or other energy source 56 is provided and delivered to the tissue in this region of the uppermost portion to treat the tissue and region in the same manner as described above with respect to fig. 32. It is contemplated that the wavelength of the laser or other energy is selected to match the IR absorption peak of the water residing in the mucus to heat the tissue and stimulate HSP activation or production and promote protein repair, with its attendant benefits.

Referring now to fig. 33, the colonoscope 54 may have its flexible light pipe 52 inserted through the anus and rectum 70 and into the large or small intestine 72, 74 to deliver the selected laser or other energy source 56 to the area and tissue to be treated, as shown. This can be used to help treat colon cancer as well as other gastrointestinal problems.

Typically, the procedure can be performed similar to a colonoscopy, in that to clear the bowel of all stool, the patient will lie on his side and the physician will insert the long and thin light pipe portion 52 of the colonoscope 54 into the rectum and move it into the region of the colon, large intestine 72 or small intestine 74 to the area to be treated. The physician can view the path of the inserted flexible member 52, and even the tissue at the end of the colonoscope 54 located in the intestine, through the monitor to view the area to be treated. The distal end 76 of the endoscope would be directed to the area to be treated using one of the other optical fibers or light pipes and the laser or other radiation source 56 would be delivered through one of the light pipes of the colonoscope 54 to treat the area of tissue to be treated, as described above, to stimulate HSP activation or production in the tissue 58.

Referring now to fig. 34, in another example, the present invention may be advantageously employed in the gastrointestinal tract, such as the condition of the Gastrointestinal (GI) tract often referred to as the "leaky gut" syndrome, marked by inflammation or other metabolic dysfunction. Since the gastrointestinal tract is susceptible to metabolic dysfunction, similar to the retina, it is expected that it will respond well to the treatment of the present invention. This may be performed by sub-threshold, diode micro-pulse laser (SDM) therapy as described above, or by other energy sources and devices as described herein and known in the art.

With continued reference to fig. 34, a flexible light pipe 52 of an endoscope or the like is inserted through the patient's mouth 64, through the throat and tracheal region 66 and into the stomach 78, with its distal end 64 directed toward the tissue 58 to be treated, and the laser or other energy source 56 directed at the tissue 58. One skilled in the art will appreciate that a colonoscope may also be used and inserted through the rectum 70 and into the stomach 78 or any tissue between the stomach and rectum.

If necessary, chromophoric pigments can be delivered orally to gastrointestinal tissue to enable absorption of radiation. For example, if 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 may be tuned to a slightly longer wavelength at the absorption peak of water, thereby eliminating the need for an externally applied chromophore.

The present invention also contemplates the use of a capsule endoscope 80, such as that shown in fig. 35, to provide a source of radiation and energy in accordance with the present invention. Such capsules have a small size, e.g., about 1 inch long, to be swallowed by a patient. As the capsule or pill 80 is swallowed and enters the stomach and passes through the gastrointestinal tract, when in place, the capsule or pill 80 may receive power and signals, such as through an antenna 82, to activate an energy source 84, such as a laser diode and associated circuitry, and a suitable lens 86 focuses the generated laser or radiation through a radiation transparent cover 88 and onto the tissue to be treated. It should be understood that the location of capsule endoscope 80 may be determined in a variety of ways, such as external imaging, signal tracking, or even by a miniature camera with a light through which a physician observes an image of the gastrointestinal tract through which pill or capsule 80 is currently passing. The capsule or pill 80 may have its own power source, such as by means of a battery, or power supplied externally through an antenna, to cause the laser diode 84 or other energy generating source to create the desired wavelength and pulse energy source to treat the tissue and area to be treated.

As with retinal treatments in previous applications, the pulsed radiation is used to take advantage of the micro-pulse temperature spikes and associated safety and the power can be adjusted to make the treatment completely harmless to the tissue. This may include adjusting the peak power, pulse time, and repetition rate to give a peak temperature rise on the order of 10 ℃ while keeping the long-term temperature rise below the FDA-specified limit of 1 ℃. If delivery in pill form 80 is used, power may be provided to the device by a small rechargeable battery or by wireless inductive excitation, etc. Heating/stressing tissues will stimulate the activation or production of HSPs and promote protein repair, as well as its additional benefits.

From the above examples, the techniques of the present invention are limited to the treatment of conditions at near body surfaces or internal surfaces that are readily accessible by optical or other optical delivery devices. The reason for applying SDM or PEMR to activate HSP activity is limited to the near surface or optically accessible areas of the body is that the absorption length of IR or visible radiation in the body is very short. However, tissues or conditions deeper within the body may benefit 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, such as microwaves, which have a longer absorption length in body tissue. Pulsed ultrasound is often preferred over RF electromagnetic radiation to activate remedial HSP activity in abnormal tissue inaccessible to surface SDMs and the like. Pulsed ultrasound sources may also be used for anomalies at or near the surface.

Referring now to fig. 36, specific regions deep in the body can be targeted specifically using ultrasound, microwave or radio frequency by using one or more beams that are focused at target sites, respectively. Then, pulsed heating will be primarily only in the target region where the beams are focused and overlapped.

As shown in fig. 36, an ultrasound transducer 90 or the like generates a plurality of ultrasound beams 92 which are coupled to the skin by an acoustic-impedance-matched gel and which penetrate the skin 94 and pass through the intact tissue located in front of the focal point of the beams 92 to a target organ 96, such as the liver as shown, and specifically to the target tissue 98 to be treated, where the ultrasound beams 92 are focused. As described above, the pulsed heating will then only occur at the target focal region 98 where the focused beam 92 overlaps. Tissue in front of and behind the focal zone 98 will not be significantly heated or affected.

The present invention contemplates not only treating surface or near-surface tissue, for example, by using a laser or the like, treating deep tissue using, for example, a focused ultrasound RF or microwave beam, but also treating blood disorders, as well as other body fluid disorders, such as sepsis. As indicated above, focused ultrasound therapy can be used both for superficial and deep body tissues, and in this case also for treating blood. However, it is also contemplated that SDM and similar PEMR therapies, which are generally limited to surface or near-surface treatments of epithelial cells and the like, are selected for treating blood or fluid disorders in areas accessible to blood or fluid through a thinner layer of tissue, such as an earlobe.

Referring now to fig. 37 and 38, treatment of a blood disorder simply requires delivery of an SDM or other electromagnetic radiation or ultrasonic pulse to the earlobe 100, wherein the SDM or other radiant energy source can pass through the earlobe tissue and into the blood passing through the earlobe. It should be appreciated that this method may also occur in other areas of the body where blood flow is high and/or near the surface of the tissue, such as the interior of a fingertip, mouth or throat, etc.

Referring again to fig. 37 and 38, the earlobe 100 is shown adjacent to a holding device 102 configured to transmit SDM radiation or the like. This may be done, for example, with one or more laser diodes 104 that will deliver the desired pulses and desired frequency of pulse trains to the ear lobe 100. Power may be provided, for example, by the lamp driver 106. Alternatively, the lamp driver 106 may be an actual laser source that is transmitted to the earlobe 100 through suitable optics and electronics. The holding device 102 will only be used to hold the patient's ear lobe and limit the radiation to the patient's ear lobe 100. This may be performed by mirrors, reflectors, diffusers, etc. This may be controlled by a control computer 108 which will be operated by a keyboard 110 or the like. The system may also include a display and speaker 112 if desired, for example if the procedure is to be performed by an operator at a distance from the patient.

As described above, although fig. 37 and 38 are shown for exemplary purposes to illustrate treatment of bodily fluids, i.e., blood, through an easily accessible external ear lobe 100, it should be understood that the pulsed energy source of the present invention can be applied to other external regions of the body, internal regions of the body, and using a variety of energy sources, including lasers, radio frequencies, microwaves, and ultrasound. Furthermore, the invention is not limited to the treatment of blood and blood diseases, but other body fluids such as lymph etc. may also be applied. The type of body fluid being treated may determine the area where treatment occurs, for example when treating lymph fluid, applying an energy source in the armpits, tonsils, etc.

Although not specifically described above, it should be understood that different diseases or potential diseases may be treated in different regions of the body, depending on the disease and target tissue to be treated for therapeutic purposes or for prophylactic or protective treatment. For example, IPF can be locally applied via bronchoscope by PEMR infrared laser therapy. Heart disease can also be treated by bronchoscopy, as the heart is close to the bronchial tree and lungs. Alternatively, as described above, the heart, lungs, etc. may be treated using PEMR radio frequency, ultrasound, or microwave due to the small infrared absorption length. An additional advantage would be that there would be no need to insert a bronchoscope into the patient's lungs, resulting in discomfort.

Again, the type of treatment selected and the procedure and parameters may vary depending on the location of the chronic progressive disease. For example, alzheimer's disease can be treated by applying RF to the brain. A person suffering from or at risk of cancer may, in accordance with the invention, apply a source of energy, whether it be tissue or blood (typically not cancer itself, as activation of HSPs in cancer cells may enhance survival and growth of the cancer; but rather treat components of the immune system to enhance their effectiveness against cancer), to the organ or region of the body in question. Even mental conditions such as depression may be treated according to the present invention.

The present invention also contemplates that the time course, and possibly the power, and other energy and operating parameters may need to be varied depending on the tissue, organ or region of the body to be treated. For example, for idiopathic pulmonary fibrosis and other lung diseases, it may be desirable to alter such parameters as convective airflow can cool lung tissue. Letting an individual exhale and hold his breath for a few seconds can also change these energy parameters, since the inflated lungs have a conductivity of 0.2S/m, whereas the deflated lungs have a conductivity of twice, i.e. 0.41S/m, and the absorption length is inversely proportional to the square root of the conductivity. The important aspect is to heat the tissue or body fluid quickly to about 11 ℃ while maintaining a lower temperature, e.g. below 6 ℃ or even 1 ℃ during a few minutes, e.g. 6 minutes. This would provide therapeutic benefits such as activation of HSPs without damage to body fluids, cells and tissues.

Referring now to fig. 39, the present invention contemplates that some diseases or risks of diseases may require treatment of multiple areas of the body. For example, diabetes can be treated by applying microwaves, RF, etc. to many areas of the body and possibly the entire body. In addition, an individual may have or be at risk of having a variety of chronic progressive diseases, which may require treatment of different areas of the body. Moreover, since the course of treatment according to the invention appears to have only beneficial therapeutic and protective results, without permanently damaging or destroying the cells or tissue, the entire body can be treated as healthy cells and the tissue will not be negatively affected by the application of the pulsed energy source applied according to the invention, while those that are damaged will benefit.

Accordingly, with continued reference to FIG. 39, the present invention contemplates a device 114 that can hold and/or support an entire body 116, such as by a platform 118 on which an individual lies. However, it should be understood that the individual may be in a different position, such as standing, and does not necessarily need to lie down. The device 114 will include a pulsed energy emitter 120 that can emit a pulsed energy source having the parameters described above to treat various types of tissues, organs, fluids, etc. of an individual. This may be, for example, with microwaves, Radio Frequency (RF) and/or ultrasound, or even using a light source to treat bodily fluids outside of the individual's body or adjacent to such surfaces. Fluids, problematic organs, or other tissues may be treated accordingly. Indeed, as described above, to treat the entire body, the emitter 120 may be moved to different regions of the body, e.g., progressively or in a predetermined manner, e.g., along the track 122, to more quickly treat a desired target tissue or target bodily fluid region and/or the entire body by heating the region to a predetermined temperature, while maintaining the predetermined lower temperature during a longer period of time. The whole body treatment may be the sum of local treatments. This would be, for example, a way to treat diabetes and other similar diseases that affect the entire body or multiple regions of the body. This can also be, for example, a system and method for the protective and prophylactic treatment of an individual's entire body, e.g., on a time basis.

The proposed treatment using electromagnetic or ultrasound pulse trains has two main advantages compared to previous treatments comprising a single short or sustained (long) pulse. First, the short (preferably sub-second) single pulse in this column activates cell reset mechanisms such as HSP activation, which have a larger reaction rate constant than those operating on a longer time scale (minutes or hours). Second, repetitive pulses in therapy provide large thermal peaks (of the order of 10000) that allow the cellular repair system to overcome the activation energy barrier that separates dysfunctional cellular states from desired functional states relatively quickly. The end result is a "reduced therapeutic threshold" in the sense that a lower average power applied and total energy applied can be used to achieve the desired therapeutic goal.

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

Claims

1. A method for providing a protective treatment to a biological tissue or fluid having or at risk of having a chronic progressive disease, comprising the steps of:

providing a pulsed energy source having energy parameters including wavelength or frequency, duty cycle, and pulse train duration selected to raise the temperature of the target tissue or body fluid to 11 degrees celsius to achieve a therapeutic or prophylactic effect, wherein the average temperature rise of the target tissue or body fluid is maintained at or below a predetermined level over a period of minutes so as not to permanently damage the target tissue or body fluid; and

the pulsed energy source is applied to a target tissue or target fluid having or at risk of having a chronic progressive disease to therapeutically or prophylactically treat the target tissue or target fluid.

2. The method of claim 1, wherein the step of applying comprises the step of stimulating heat shock protein activation in the target tissue or target fluid.

3. The method of claim 1, comprising the steps of: the energy parameters of the pulsed energy source are selected to raise the temperature of the target tissue or target fluid to between 6 degrees celsius and 11 degrees celsius at least during application of the pulsed energy source to the target tissue or target fluid.

4. The method of claim 1, wherein the average temperature rise of the target tissue or target fluid is maintained at 6 degrees celsius or less over a period of minutes.

5. The method of claim 4, wherein the average temperature rise of the target tissue or target fluid is maintained at about 1 degree Celsius or less over a period of minutes.

6. The method of claim 5, wherein the average temperature of the target tissue or target fluid is maintained at 1 degree Celsius or less during a 6 minute period.

7. The method of claim 1, wherein the energy parameters of the pulsed energy source are selected to absorb 20 to 40 joules of energy per cubic centimeter of the target tissue or target fluid.

8. The method of claim 1, wherein the step of applying the pulsed energy source comprises inserting a device into a body cavity to apply the pulsed energy source to the target tissue or target fluid.

9. The method of claim 1, wherein the step of applying the pulsed energy source comprises directing the pulsed energy source to an exterior of a body adjacent to the target tissue or a target bodily fluid supply having a surface proximate to a region of the exterior of the body.

10. The method of claim 1, comprising the step of determining that the target tissue or target fluid has or is at risk of having a chronic progressive disease.

11. The method of claim 1, wherein the pulsed energy source is applied to a plurality of target tissue regions, and wherein adjacent target tissue regions are separated by at least a predetermined distance to avoid thermal tissue damage.

12. The method of claim 1, wherein the pulsed energy source comprises a laser, microwave, radio frequency, or ultrasound.

13. The method of claim 12, wherein the pulsed energy source comprises a radio frequency between 3 and 6 megahertz, a duty cycle between 2.5% and 5%, and a pulse train duration between 0.2 and 0.4 seconds.

14. The method of claim 13, wherein the radio frequency is generated by a device having a coil radius between 2 and 6 millimeters and between 13 and 57 ampere turns.

15. The method of claim 12, wherein the pulsed energy source comprises a microwave frequency between 10 to 20GHz, a pulse train duration between 0.2 and 0.6 seconds, and a duty cycle between 2% to 5%.

16. The method of claim 15, wherein the microwave has an average power of between 8 and 52 watts.

17. The method of claim 12, wherein the pulsed energy source comprises a pulsed light beam having a wavelength between 530 nanometers and 1300 nanometers, a duty cycle of less than 10%, and a pulse train duration between 0.1 and 0.6 seconds.

18. The method of claim 17, wherein the pulsed light beam has a wavelength between 880 nanometers and 1000 nanometers and a power between 0.5 and 74 watts.

19. The method of claim 12, wherein the pulsed energy source comprises pulsed ultrasound having a frequency between about 1MHz and 5MHz, a column duration between 0.1 and 0.5 seconds, and a duty cycle between 2% to 10%.

20. The method of claim 19, wherein the ultrasound has a power between 0.46 and 28.6 watts.

21. A method for providing a protective treatment to a biological tissue or fluid having or at risk of having a chronic progressive disease, comprising the steps of:

determining that the target tissue or target bodily fluid has or is at risk of having a chronic progressive disease;

providing a pulsed energy source of laser, microwave, radiofrequency or ultrasound having energy parameters including wavelength or frequency, duty cycle and pulse train duration, the energy parameters being selected to raise the temperature of the target tissue or target fluid to between 6 and 11 degrees celsius at least during application of the pulsed energy source to obtain a therapeutic or prophylactic effect, wherein the average temperature rise of the target tissue or target fluid is maintained at or below 6 degrees celsius over a period of minutes so as not to permanently damage the target tissue or target fluid; and

applying the pulsed energy source to the target tissue or the target fluid determined to have or at risk of having a chronic progressive disease to therapeutically or prophylactically treat the target tissue or target fluid.

22. The method of claim 21, wherein the step of applying comprises the step of stimulating heat shock protein activation in the target tissue or target fluid.

23. The method of claim 21, wherein the average temperature of the target tissue or target fluid is maintained at 1 degree celsius or less during a 6 minute period.

24. The method of claim 21, wherein parameters of the pulsed energy source are selected to absorb 20 to 40 joules of energy per cubic centimeter of the target tissue or target fluid.

25. The method of claim 21, wherein the step of applying the pulsed energy source comprises inserting a device into a body cavity to apply the pulsed energy source to the target tissue or target fluid.

26. The method of claim 21, wherein the step of applying the pulsed energy source comprises directing the pulsed energy source to an exterior of a body adjacent to the target tissue or a target bodily fluid supply having a surface proximate to a region of the exterior of the body.

27. The method of claim 21, wherein the pulsed energy source is applied to a plurality of target tissue regions, and wherein adjacent target tissue regions are separated by at least a predetermined distance to avoid thermal tissue damage.

28. The method of claim 21, wherein the pulsed energy source comprises a radio frequency between 3 and 6 megahertz, a duty cycle between 2.5% and 5%, and a pulse train duration between 0.2 and 0.4 seconds.

29. The method of claim 28, wherein the radio frequency is generated by a device having a coil radius between 2 and 6 millimeters and between 13 and 57 ampere turns.

30. The method of claim 21, wherein the pulsed energy source comprises a microwave frequency between 10 to 20GHz, a pulse train duration between 0.2 and 0.6 seconds, and a duty cycle between 2% to 5%.

31. The method of claim 30, wherein the microwave has an average power of between 8 and 52 watts.

32. The method of claim 21, wherein the pulsed energy source comprises a pulsed light beam having a wavelength between 530 nanometers and 1300 nanometers, a duty cycle of less than 10%, and a pulse train duration between 0.1 and 0.6 seconds.

33. The method of claim 32, wherein the pulsed light beam has a wavelength between 880 nanometers and 1000 nanometers and a power between 0.5 and 74 watts.

34. The method of claim 21, wherein the pulsed energy source comprises pulsed ultrasound having a frequency between about 1MHz and 5MHz, a column duration between 0.1 and 0.5 seconds, and a duty cycle between 2% to 10%.

35. The method of claim 34, wherein the ultrasound has a power between 0.46 and 28.6 watts.