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: BR112019001348A2; WO2018031255A1; CA3030483A1; AU2017308587A1; EP3496810A4; JP2019524179A; 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

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

Technical field

The present invention relates generally to the methods for treating biological tissue or fluid.In particular, the present invention relates to for suffering from Chronic progressive disease or the method for biological tissue or fluid offer protectiveness treatment with chronic progressive disease risks.

Background technique

Chronic progressive disease (chronic progressive disease；CPD) it is currently and future is more medical treatment Health care challenge.There are many such CPD, including type-2 diabetes mellitus, Alzheimer (Alzheimer) disease, idiopathic lung fiber Change (idiopathic pulmonary fibrosis；IPF), heart disease etc..The basic reason of many diseases be it is unknown, this A little diseases are either without treating or not having optimal treatment.The some of or consistent in a short time of these diseases terminate, and Great public health problem is constituted because popularity increases.

These diseases are not only chronic and are progressive.Basic reason there are many chronic progressive disease is possible, Including infection, heredity, multifactor and immune.Although there are many different reasons by CPD, they have basic something in common.Institute The uniform characteristics of CPD are the accumulation of albumen in abnormal cell.Another common trait of all CPD is cell and organ dysfunction Imbalance increases, so as to cause failure.Another common and unification of CPD is characterized in that cell and dysfunction of organ cause and promote Into chronic inflammation.These of all CPD are characterized in vicious circle, and disease is caused to deteriorate over time.

Therefore, interrupting the circulation is vital for improving the course of disease.A kind of method for treating CPD is gene therapy, It needs to identify and repairs or replace the dcc gene for leading to disease.But, for some CPD, gene defect is unknown.It is right In other CPD, identical disease may be led to there are many latent gene defect.For example, retinal pigment degeneration (retinitis Pigmentosa) can be caused by arbitrary more than 150 kinds of different genes defects.This potential a variety of essential defect becomes gene therapy It obtains difficult.

The method of another kind treatment CPD is drug therapy, and generally attempting to targeting is considered most important to lysis Specific cells albumen, to inhibit or enhance their effect.But, due to having 2000 kinds of differences of estimation in typical cells Protein types, have 10⁶⁸⁰Kind potential interaction, thus successfully, clinically effectively without unacceptable negative interaction Targeted drug treatment is difficult.

The method of another kind treatment CPD is non-specific anti-inflammatory treatment.These include various steroidals and non-steroidal anti-inflammatory agent And immunosuppressive drug.But, anti-inflammatory agent is in many of CPD disadvantage.Since they do not solve the basic reason of disease, it Must be used for a long time and have limited effect.Due to they binding mode and long-time service needs, treatment Negative interaction and complication limit their effectiveness.Immunosuppressive drug and anti-inflammatory agent have same limitation.But, due to it Also change the normal function of immune system in addition to lysis, therefore they can cause further complication, including its Its diseases complex and tumor are formed.Radiotherapy is for example another method for treating CPD using radiation, x-ray.It has with Use anti-inflammatory and similar immunosuppressive drug effect.But, it can also bring more problematic negative interaction, even if these negative interactions Treatment stop after also deteriorating as time goes by, if therefore expection long-term surviving, often make the radiotherapy can not Receive.

The newer method of the another kind of CPD treatment is to identify and inhibit to manage albumen.Such management protein for treatment attempts By finding key and common albumen or enzyme for several disease states regardless of basic reason and inhibiting in various ways They are solved the problems, such as brought by gene, drug and anti-inflammatory/immunosuppressive therapy.If may be due to individually managing albumen Dry disease condition is for example various and the core of other unrelated cancer developments, therefore blocks this key protein may be than more Disease target treatment has wider treatment use.But, if managing protein for treatment with albumen sheet as targeting and equally having The usual limitation for having targeted drug to treat, accessory problem are to trigger compensation mechanism and for example raise to cause to pharmaceutically-active permanent It is insensitive.Moreover, if managing protein for treatment equally has gene therapy to generate the transcription of albumen and translation mechanism as targeting Usual limitation.Such management protein for treatment also equally there is targeted drug as described above to treat possessed problem.

Stem cell transplantation (stem cell transplantation；SCT) be CPD treatment another method.SCT examination Figure to tissue or in the region of tissue by using new functional organization to substitute dead or functional disturbance stem cell transplantation Tissue.SCT is extremely complex and expensive, has significant risk and bad therapeutic effect.Although the public is very interested, SCT is arrived It is invalid so far.

Existing method recited above for CPD treatment has limited success and effectiveness, therefore most of CPD are current It does not treat or is only Palliative or invalid treatment.These treatments have limited success and effectiveness because of actual limitation, These limitations include unknown or many reasons, cost, time and non-physiology (non-natural and artificial) binding mode, According to definition, these modes are superimposed new drug-induced morbid state on CPD.Accordingly, the ideal treatment of CPD should be independently of Basic reason is physiological, and therefore not only effectively but also tolerance is well without side effect, and more by the circulating cycle Point includes directly intervening in major defect distal end and capable of breaking pernicious CPD circulation, to obtain maximum effect.The present invention meets this It needs and other associated advantages is provided.

Summary of the invention

The present invention relates generally to for the life with chronic progressive disease or the risk with chronic progressive disease Object tissue or fluid provide the method for protectiveness treatment.The present invention applies impulsive energy source to biological tissue or fluid, to increase The temperature of the target tissue or target fluid and the activation for stimulating heat shock protein, to promote albumen reparation without injury tissue.

According to the present invention, impulsive energy source is provided, having includes wavelength or frequency, duty ratio (duty cycle) and arteries and veins The energy parameter of punching column duration (pulse train duration).The impulsive energy source may include laser, microwave, radio frequency Or ultrasound.The energy parameter is selected to the target group at least during applying the impulsive energy source to the target tissue or target fluid It knits or target rehydration temperature is increased to 11 DEG C, usually between 6 DEG C to 11 DEG C, to obtain therapeutic or prophylactic effects.In number The average temperature rising of the tissue or target fluid is held in or lower than predeterminated level during minute, thus will not the permanent damage target group It knits or target fluid.For example, the average temperature rising of the target tissue or target fluid can be held in 6 DEG C or lower during several minutes. In general, during several minutes such as 6 minutes durations, the average temperature rising of the target tissue or target fluid is held in about 1 DEG C or more It is low.

The impulsive energy source may include radio frequency.The radio frequency usually between 3 to 6 megahertzs (MHz), and have 2.5% to Duty ratio between 5%, and the spike train duration between 0.2 to 0.4 second.The radio frequency can be by having in 2 and 6 millis Coil radius between rice and the device between 13 and 57 ampere-turns generate.

When the impulsive energy source includes microwave frequency, the frequency usually between 10 to 20 gigahertz (GHZ)s (GHz), hold by spike train It is continuous that the time is between 0.2 and 0.6 second and duty ratio is between 2% and 5%.The microwave can have flat between 8 and 52 watts Equal power.

When the impulsive energy source is pulsed light beam, the light beam can have wavelength between 530 nanometers to 1300 nanometers, Duty ratio less than 10% and the spike train duration between 0.1 and 0.6 second.Preferably, the pulsed light beam has Wavelength between 800 nanometers and 1000 nanometers, and the power between 0.5 and 74 watt.

When the impulsive energy source includes impulse ultrasound, it usually have frequency between 1MHz and 5MHz, 0.1 with Column duration between 0.5 second and the duty ratio between 2% to 10%.The ultrasound can have 0.46 and 28.6 watt it Between power.

It can determine the target tissue or target fluid with chronic progressive disease or with the risk for suffering from chronic progressive disease. Apply the target tissue from the pulse to the risk with chronic progressive disease or with the chronic progressive disease of trouble or target fluid Energy source, with the therapeutic or prophylactic treatment target tissue or target fluid.The energy parameter of the impulsive energy source can be chosen with The target tissue or target fluid per cubic centimeter is set to absorb 20 to 40 joules of energy.It, can be to body to apply the impulsive energy source Insertion apparatus in chamber, to apply the impulsive energy source to the target tissue or target fluid.Alternatively or additionally, by the pulse energy Source is guided to the outside of body, and adjacent to the target tissue or the target body liquid with the surface close to the outside of the body is supplied. The impulsive energy source can be applied to multiple target tissue regions.Adjacent target tissue region is separated at least one preset distance, to keep away Exempt from hot tissue damage.

It is believed that by selectively and controllably during short time period the target tissue or fluid temperature (F.T.) being increased to make a reservation for The average temperature rising of the tissue is held in predetermined temperature during longer period simultaneously by temperature range, and method of the invention provides Beneficial effect.These effects can respond infection or other abnormal increase bodily tissues or fluid by inducing heat shock response In heat shock protein number or activity cause.The present invention executes the method in a controlled manner, in case damage or destruction should The region of tissue, fluid or body being treated.

From below with reference to illustrating detailed description made by the attached drawing of the principle of the present invention, other feature of the invention and Advantage will become clearer.

Detailed description of the invention

Attached drawing is used to illustrate the present invention.In the drawings:

Fig. 1 shows the schematic views to generate the system of the impulsive energy source of laser beam form according to the present invention；

Fig. 2 shows the optical schematic views to generate laser geometric pattern according to the present invention；

Fig. 3 shows the alternate embodiment for treating the system of tissue and fluid to generate laser beam according to the present invention Schematic views；

Fig. 4 shows the signal for treating another embodiment of the system of tissue to generate laser beam according to the present invention View；

Fig. 5 shows the top view of used optical scanner mechanism according to the present invention；

Fig. 6 shows the optical cable of the optical scanner mechanism of Fig. 5, to illustrate its different component；

Fig. 7 show according to the present invention to treat the laser facula of the example geometrical pattern grid of target tissue irradiation by Control offset；

Fig. 8 is shown uses the signal for controllably being scanned the geometric object in the form of the line for treating target tissue to regard according to the present invention Figure；

Fig. 9 shows similar with Fig. 8 but shows that rotation geometry line or item are according to the present invention with the schematic views for the treatment of region；

Figure 10 and Figure 11 shows that the mean power of laser source compares the source radius and the figure of spike train duration of laser；

Figure of Figure 12 and Figure 13 displays temperature according to the time of the decaying of laser source radius and wavelength；

Figure 14 to Figure 17 shows the figure for different radio frequency, duty when peak ampere the number of turns of coil radius；

Figure 18 shows the figure for comparing the time of temperature rise decaying of radio-frequency coil radius；

Figure 19 and Figure 20 shows that averaged microwave power compares the figure of microwave frequency and spike train duration；

Figure 21 shows the figure of the time of the temperature damping for different microwave frequencies；

Figure 22 shows that averaging ultrasound source power compares the figure of frequency and spike train duration；

Figure 23 and Figure 24 shows the figure of the time of the temperature damping for different supersonic frequencies；

Figure 25 shows that the volume of focus heating zone compares the figure of supersonic frequency；

The temperature of Figure 26 display source of ultrasonic energy figure compared with the equation in pulse duration；

The amplitude of the logarithm of Figure 27 and Figure 28 display damage and HSP activation Arrhenius (Arrhenius) integral is with temperature Degree and the figure of pulse duration variation and variation；Figure 29 shows the photogenerated list for generating commutator pulse sequence according to the present invention The schematic views of member, the photogenerated unit have the light pipe extended from；

Figure 30 is shown according to the present invention to the cross-sectional view of the light stimulus conveying device of target tissue conveying electromagnetic energy；

Figure 31 show the cutting for being inserted into nasal cavity and treating the end of endoscope of tissue therein according to the present invention and Schematic views；

Figure 32 shows in the bronchus for extending through tracheae and entrance lung according to the present invention and provides it the branch gas for the treatment of The signal of Guan Jing and partial sectional view；

Figure 33 is shown provides the schematic views of the Sigmoidoscope of light stimulus to the intestines of body or colon regions according to the present invention；

Figure 34 shows the schematic views for being inserted into stomach and providing it the endoscope for the treatment of according to the present invention；

Figure 35 shows the partial sectional three-dimensional view of used capsule endoscope according to the present invention；

Figure 36 is shown according to the present invention for treating the signal view of the pulsed high-intensity focused ultrasound of the tissue of body interior Figure；

Figure 37, which is shown, provides the schematic views for the treatment of to the blood flow of patient by ear-lobe according to the present invention；

Figure 38 shows and is being controlled according to the present invention by ear-lobe to stimulation of the invention used in blood conveying light stimulus Treat the cross-sectional view of device；And

Figure 39 is shown according to the present invention for treating the signal and solid of the device of personal multiple regions or entire body View.

Specific embodiment

As the present invention that illustrates and show comprehensively herein reside at it is chronic to suffering from chronic progressive disease or have The biological tissue of the risk of progressive disease or fluid are provided in the method and system of protectiveness treatment.According to the present invention, pulse Energy source has the energy parameter including wavelength or frequency, duty when spike train duration, which is selected to Target tissue or target rehydration temperature are increased to 11 degrees Celsius within short several seconds or shorter periods, while several minutes of phases Between the average temperature rising of the tissue or target fluid is held in or lower than predeterminated level, thus will not the permanent damage target tissue or target Fluid.To the target tissue or target fluid being determined with chronic progressive disease or with the risk for suffering from chronic progressive disease Apply the impulsive energy source.This determination can iconography, serology, immunology or other exceptions it is detectable before make or can Preventative execution.This determination can be by finding out whether patient there is the risk of chronic progressive disease to reach.As substitution or Additional, the inspection of patient or the result of test may be abnormal.Executable specific test such as genetic test, to confirm that patient has There is the risk of chronic progressive disease.

It is believed that the present invention is by stimulating target tissue to the mechanism of therapeutic or prophylactic treatment biological tissue or fluid Or the heat shock protein activation in target fluid.Heat shock protein (heat shock protein；HSP all lifes) are prevalent in In highly conserved enzyme family in the presence of all cells of object.The accounting of this all albumen in the presence of given cell Up to 40%.HSP is active and vital in terms of maintaining normal cell function and stable state.HSP has many passes Key function, one of them is to protect cells from any type of fatal injury and repair sub- lethal (sublethal) damage.

Although chronic inflammation be it is pathologic and destructive, acute inflammation can be for prosthetic.Acute inflammation can be rung Emergency damage occurs.The common injury for needing to repair is usually related to cell and tissue damage such as wound.According to damage The function sensitive of seriousness and tissue may cause key function forfeiture although wound reparation.Incomplete reparation is held Continuous or duplicate damage may cause such as the chronic inflammation in CPD.

By the complex physiologic for continuing to monitor and repairing deficient protein and potential threat (such as bacterium, virus and tumor) formation Process maintains normal healthy state.These normal physiological processes and its effect are preferably, because of good health and function It is the result of their normal function.Although the normal function of these physiology courses is ideal, such steady-state process itself It is not always perfect effective.Potential threat and abnormal may escape are detected or beyond repair ability.The mistake of monitoring and response Losing may be caused by many reasons, including disease causes immunosupress, (such as be occurred by hiding antigenic stimulus to escape detection In particular cancers and retrovirus), and lower than symptom identification and the horizontal morbidity and progress of activation.

HSP is the first step in acute inflammatory process.By threatening activation HSP to cause a series of successors, cause to change Into cell function, reduction chronic inflammation and prosthetic immunological regulation.Effective HSP activation saves the life of cell simultaneously Make cell function normalization, also referred to as homeotrophy (with supporting).Unexpected and serious stimulation is activated with feeding formula HSP Most effective stimulant.The stimulation for slowly carrying out waiting a moment property is not effective activator of HSP response.Therefore, CPD will not be stimulated The repair response of HSP activation.In some CPD, such as diabetes and Alzheimer disease, HSP function itself may become abnormal.

But, in general, by identifying and repairing abnormal cell albumen without considering the reason for keeping them abnormal come normalization Cell function, HSP make cell function normalization independently of abnormal reason.HSP has the ability to restore every kind of albumen into correct to it State or eliminate unrepairable albumen, to be replaced.It is perfect, and do not have since HSP response is physiological There is ill-effect, repairs the thing being destroyed without considering the reason of destroying, the repair response of HSP is wholly adapted to lysis. So with the non-specific trigger that formula HSP activation is disease specific reparation is supported.

Inventor is it has been found that the high thermostimulation HSP of cell by electromagnetic radiation induced acute but sub- lethal is activated It is feasible for not having cell or tissue damage.Therefore, in the case where no cell death or tissue damage, it can trigger acute inflammation The a succession of physiology reparation and support together that disease responds, without bad therapeutic effect.Cause in the case where no tissue damage Acute inflammation can be considered " like " acute inflammation.That is, can cause with feeding formula cell high fever complete and only beneficial Acute inflammation response, " like " it is caused by tissue damage, but in the case where no tissue damage.It has been found that with supporting The most safe and most effective stimulation of formula HSP activation is by pulsed electromagnetic radiation (pulsed electromagnetic radiation；PEMR).Pulse allows to threaten the emergentness stimulated and the significant increase of seriousness without killing target cell, thus Increase the HSP activation cured in response with feeding formula to the maximum extent.Different types of PEMR is most suitable for different biologic applications, packet Include light, laser, radio wave and microwave and ultrasound.

Eyes are the organs that function is most sensitive in body.There are several CPD to influence retina, they usually have CPD jointly Typical characteristics.Correspondingly, the CPD of retina may act as the model of the CPD in other places in body.A large amount of patients for many years Clinical experience discovery treats (micropulsed laser using low-intensity/high density subthreshold value diode pulse laser treatment；SDM) PEMR of form have been demonstrated effectively to treat, prevent, slow down, reverse or prevent every kind of retina it is main The progress of chronic progressive disease, without considering reason.These include age-dependent, hereditary, metabolism and have Change the disease of the unknown etiology of very big genotype and phenotype (phenotype).Although retina has heat sensitivity, by In the selection of the operating parameter of PEMR, therefore SDM does this and operates without any known bad therapeutic effect, thus is complete It is executed in the case where safety.

About traditional retinal photocoagulation, doctor must deliberately create retinal damage as the elder generation effectively treated in treatment Certainly condition.But, inventor speculates, by solidifying retinal pigment epithelium (the retinal pigment caused of traditional light epithelium；RPE) treatment that cell factor (cytokine) generates changes from the cell at conventional laser calcination edge, The irradiation of their stimulated lights influences but is not irradiated with a laser kill.Inventor creates energy parameter, and energy parameter creation is " true Subthreshold value light coagulate (subthreshold photocoagulation) ", the light is solidifying be it is invisible and including by it is any Perception method (such as FFA, FAF, retrograde FAF or even DS-OCT) all unrecognizable laser therapy, and absolutely do not generate It is can be detected in treatment by any way or detectable by any known any time of detection mode afterwards The retinal damage arrived, but still generate the benefit of traditional retinal photocoagulation.To this in US publication 2016/0346126A1 It discusses, content is by reference to being incorporated herein.

It is solidifying to obtain the effective light of true subthreshold value to determine various parameters, including provides enough power to generate effectively Treatment, but not Tai Gao is so that cause tissue damage or destruction.It has been found that low between 100 watts to 590 watts every square centimeter The intensity or power of 810 nanometer laser beam of duty ratio are effective and safe.For 810 nanometers of micropulse diode lasers, The particularly preferred intensity or power of laser beam are about 250 to 350 watts every square centimeter.

The longer irradiation duration of power limit needs of current micropulse diode laser, but it is important that Heat generated can dissipate towards the not illuminated tissue at the edge in laser facula, in order to avoid damage or destruction cell or group It knits.It has been found that the radiation laser beam of 810 nanotube diode lasers should have 500 milliseconds or shorter of irradiation envelope, preferably About 100 to 300 milliseconds.If micropulse diode laser becomes more high-power, irradiation duration can be accordingly reduced.It has sent out Existing, invisible phototherapy or true subthreshold value light according to the present invention is solidifying can be in the model for example from 532 nanometers to 1300 nanometer It encloses and is executed under interior various optical maser wavelengths.Different wave length uses the preferred intensity or power that can influence laser beam and irradiation The envelope duration to not damage retinal tissue, but still obtains therapeutic effect.In general, the duration of laser pulse is small In 1 millisecond, and the duration is usually in 50 microseconds between 100 microseconds.

Another parameter of the invention is between duty ratio or the frequency or continuous impulse of micropulse column when using a laser Thermal relaxation (thermal relaxation) time length.It has been found that 10% or the use of higher duty ratio can increase The risk of lethal cellular damage.Therefore, using the duty ratio less than 10% and it is preferably about 5% or smaller duty ratio, because Enough heat liters are provided in the treatment to be proved this parameter, lower than the level that expection can generate lethal cellular damage.It accounts for For sky than smaller, the irradiation envelope duration can be longer.For example, irradiation envelope in some cases is held if duty ratio is less than 5% The continuous time can be more than 500 milliseconds.

Consequently, it was found that following key parameter, creates in retinal tissue harmless, true with according to the present invention Subthreshold value light is solidifying:

A) there are at least 532 nanometers and the preferably light beam of the wavelength between 532 nanometers to 1300 nanometers；

B) low duty ratio is, for example, less than 10% and preferably 5% or smaller；

C) small luminous spot dimension, to reduce heat accumulation to the maximum extent and ensure the uniform heat point in given laser facula Cloth, to increase heat dissipation to the maximum extent；And

D) enough power, to generate the retinal laser irradiation between 18 to 55 times of MPE, to generate 7 DEG C to 14 DEG C RPE temperature rise and 100 to 590W/CM²Between retina irradiation level.

By using these above-mentioned parameters, the harmless but upper effective true subthreshold value for the treatment of or invisible light can get Solidifying phototherapy treatment, it is achievable, it has been found that it generate the shortcomings that traditional light coagulates the benefit of phototherapy but avoids traditional phototherapy and Complexity.Bad therapeutic effect is completely eliminated, and function retina is retained rather than sacrifices.Moreover, entire retina can be made It is exposed to impulsive energy source of the invention, to allow fully rather than part or partly preventative and therapeutic treatment suffer from The eyes of retinal disease.

In retina, the clinical benefit for generating SDM is activated by Asia morbid state photo-thermal RPE HSP.In the RPE of functional disturbance In cell, the cytokine-expressing for leading to normalization and therefore improved retinal structure and function are stimulated by the HSP of SDM Energy.Since the cell normally acted on does not need to repair, the HSP in normal cell stimulates often not significant clinical effectiveness.Closely " pathology selectivity " such as SDM of infrared laser effect influence the sick cells of various cell types without influence normal cell with The clinical observation of SDM is consistent.This function is used for the eyes with chronic progressive disease for SDM and suffers from slight retina The early stage of the eyes of abnormal and slight functional disturbance and preventative-therapeutic applicability are crucial.Although SDM be it is safe, The clinical effectiveness of SDM is significant and far-reaching.For example, the progression rates of diabetic retinopathy are reduced by 85% (p by SDM =0.0001) 95% (P < 0.0001) and by the progression rates of age-related macular degeneration is reduced, improves the view mind of glaucoma The visual field (P=through function (P=0.001) and glaucoma and all retinal diseases including retinal pigment degeneration 0.0001)。

Referring now to Fig. 1, the schematic diagram of the system for realizing method of the invention is shown.The system is (usually with attached Icon note 10 indicates) it include laser console 12, such as 810 nm near-infrared micropulse diode lasers in preferred embodiment Device.The laser generates laser beam, makes the light beam as needed through Optical devices, such as an optical lens or exposure mask, Or multiple optical lenses and/or exposure mask 14.Laser-projector Optical devices 14 by shaped beam be transferred to coaxial wide area not in contact with Formula digit optical observing system/camera 16, by the eyes 18 of the laser beam light projection to patient, or as herein specifically Bright other biological target tissues or body fluid.It should be appreciated that box 16 can represent laser beam projector and observing system/camera two Person, it is practical to may include two different components when in use.Observing system/camera 16 provides feedback to display monitor 20, The display monitor may also include necessary computerized hardware, data input and control etc., to operate laser 12, Optical devices 14 and/or projection/observation assembly 16.

Referring now to Fig. 2, in one embodiment, so that laser beam 22 is passed through collimator lens 24 and is then passed through and cover Film 26.In a certain preferred embodiment, exposure mask 26 includes diffraction grating.Exposure mask/diffraction grating 26 generates geometric object, or More typically, the geometrical pattern being made of the multiple laser faculas generated simultaneously or other geometric objects.This is by multiple laser lights Beam 28 indicates.Alternatively, multiple laser facula can be generated by a plurality of optical fiber cable.The both of which for generating laser facula allows On the extremely wide treatment open country being for example made of entire retina while creating extremely large amount of laser facula.In fact, high number Purpose laser facula (possible hundreds if not thousands of or more) may cover entire eyeground and entire retina, including macula lutea and in Entreat recessed, retinal vessel and optic nerve.The purpose of method of the invention is preferably ensure target region complete and comprehensive Covering and treatment, which may include retina, not leave any part of retina, by laser so as to improve view Power.

By using have with the optical signature of the comparable characteristic size of wavelength of used laser for example by using Diffraction grating, be using quantum mechanical effects it is feasible, allow to great target region while applying extremely large amount of laser light Spot.All there is the optics geometry similar with input light beam by the independent hot spot that such diffraction grating generates, each hot spot has pole Small changed power.The result is that multiple laser faculas with enough irradiation level generate harmless but are had on big target region simultaneously The treatment use of effect.Present invention also contemplates that using the other geometric objects and pattern that generate by other diffraction optical elements.

By the laser diffraction of exposure mask 26, the periodic patterns apart from 26 certain distance of exposure mask are generated, such as the laser in Fig. 2 Shown in beam 28.Therefore single laser beam 22 is formed as into multiple (up to hundreds or even thousands of) individually laser beam 28, To create the required pattern of hot spot or other geometric objects.These laser beams 28 can be made to pass through additional lens, collimator etc. 30 And 32, to transmit the laser beam and the pattern needed for formation on the retina of patient.Such additional lens, collimator etc. 30 and 32 can also convert as needed and redirect laser beam 28.

Shape, spacing and pattern by controlling optical mask 26 can construct arbitrary graphic pattern.The pattern and irradiation hot spot can It arbitrarily creates and modifies needed for application requirement according to the expert in optical engineering field.Photoetching technique is especially in semiconductors manufacture The geometrical pattern that technology those of is developed in field while can be used to create hot spot or other objects.

Although hundreds or even thousands of simultaneously laser facula can be generated and create and be formed as being applied in The pattern of tissue, but the requirement due to not making tissue overheating, the number of the treatment hot spot or light beam that can be used simultaneously according to the present invention Mesh is restricted.Each independent laser beam or hot spot need the minimum average B configuration power during arranging the duration effective.But, together When, tissue is no more than specific temperature rise without being damaged.For example, for using 810 nm wavelength lasers, when using 0.04 (4%) when total column duration of duty ratio and 0.3 second (300 milliseconds), the number of hot spot can while generating and use From only 1 to being up to about 100.

The absorption of water increases as wavelength increases, and causes in the long path length of the vitreum before by retina Heating.For such as 577 nanometers of shorter wavelength, the absorption coefficient of the melanin of RPE can be higher, therefore laser power can be compared with It is low.For example, at 577 nanometers, it is of the invention effective to make, power can be reduced by 4 times.Correspondingly, when 577 nm wavelength lasers of use When, can only have single laser facula or be up to about 400 laser faculas, while still not damage or damaging eyes or other groups It knits.Treatment light beam or hot spot multiple while generate, such as tens or even hundreds of can be used in the present invention, because of the invention Parameter and method creation treatment is upper effective but nondestructive and the treatment of impermanent damage.

Fig. 3 is schematically shown the system of multiple light sources and the coupling of above-mentioned pattern generation optical sub-assembly.Specifically, system 10 ' is similar with system 10 described in above figure 1.The essential difference between system 10 in alternative system 10 ' and more early illustrated Being includes multiple laser console 12, and output is entered respectively in fiber coupler 34.The fiber coupler generates single defeated Out, which is passed in the laser-projector Optical devices 14 as described in system earlier.By multiple laser console 12 are coupled in single optical fiber through the realization of fiber coupler 34 known in the art.It can get for combining multiple light sources Other known mechanism simultaneously can be used it to substitute fiber coupler described herein.

In this system 10 ', multiple light sources 12 follow similar path described in more early system 10, that is, collimate, spread out It penetrates, collimate again, and guided by guiding mechanism into retina.In this alternative system 10 ', according to the light passed through Wavelength, diffraction element is acted on being different from mode described in relatively morning, so as to cause the pattern of slight variation.The variation be diffracted Light source wavelength it is in a linear relationship.In general, the difference of angle of diffraction is sufficiently small, so as to logical along identical optical path It crosses guiding mechanism 16 and guides different overlapping patterns to retina 18, for treating.The fine difference of angle of diffraction will affect How guidance pattern realizes the covering of retina.

Since gained pattern is for each wavelength meeting slight variation, realize that the sequence offsets completely covered will be for each wavelength Different.This sequence offsets can be implemented with both of which.In the first mode, while applying the light of all wavelengths, without Identical covering.Pattern is guided using the offset completely covered for the realization of one of multiple wavelength.Therefore, although institute The light of wavelength is selected to realize the complete covering of tissue regions to be treated, but the application of other wavelength obtains incomplete or overlapping Tissue coverage.Second of mode sequence applies each light source of the variation with suitable guidance pattern or different wavelength, To realize the complete covering of tissue for this specific wavelength.This mode excludes a possibility that treating simultaneously using multiple wavelength, but The optical means is allowed to realize identical covering for each wavelength.This is avoided for any optical wavelength incomplete or overlapping Covering.

It can also mix and match these modes.For example, can apply two wavelength simultaneously, a wavelength realizes complete covering And another realizes incomplete or overlapping covering, then sequence applies third wavelength and realizes complete covering.

Fig. 4 schematically shows another alternate embodiment of invention system 10 ".This system 10 " be configured as with shown in Fig. 1 System 10 it is roughly the same.Main difference is that multiple pattern generation sub-components including the specific wavelength for being tuned to light source are logical Road.Be arranged in parallel multiple laser console 12, each laser console is directly communicated to the laser-projector optics dress of their own Set 14.The laser-projector Optical devices of each channel 38a, 38b, 38c include collimator 24, exposure mask or diffraction grating 28 and again New collimator 30,32, as described in above in connection with Fig. 2-for corresponding laser console 12 specific wavelength generated tuning whole group Optical devices.Then, the output of each group Optical devices 14 is guided to beam splitter 36, with other wavelength combinations.This field Those of ordinary skill is it is known that the beam splitter reversely used can be used to multiple light beam groups being combined into single output.

Then, combination channel of the guidance from final beam splitter 36c outputs through camera 16, which applies guiding mechanism To allow the complete covering of retina 18.

In system 10 ", the optical element in each channel is after tuning to generate accurate specific pattern for the wavelength in channel. Therefore, when by all combination of channels and it is suitable when aligned, can be used single guidance pattern to realize retina for all wavelengths Complete covering.

System 10 " can be used and channel 38a, 38b, the 38c of optical wavelength as many etc. and beam splitting used in treatment Device 36a, 36b, 36c etc..

The implementation of system 10 " can reduce the number of alignment constraint using different symmetry.For example, the grid proposed Pattern is periodic in two dimension and along two dimension guidance to realize complete covering.Therefore, if the pattern in each channel and specified phase Together, then the actual pattern in each channel will not needed for identical guidance alignment pattern completely to cover for all wavelengths realization Lid.It would only need to each channel of optical alignment, to realize effective combination.

In system 10 ", each channel starts from light source 12, may be from the other embodiments such as pattern generation sub-component Optical fiber.Light source 12 is guided to optical module 14 with collimation, diffraction, collimates and guides to the beam splitter, the beam splitter again It combines in the channel with main output.

Photobiology field shows to can get different biological effects by the laser that target tissue is exposed to different wave length. By sequentially continuously applying with the interval time section that can be changed and/or with different radiation energies with similar and different wave Long multiple laser also can get identical effect.Present invention expection simultaneously or sequentially applies multiple laser, light or radiation wavelength (or mode), to increase or customize required therapeutic effect to the maximum extent.The method also reduces potentially harmful work to the maximum extent With.While optical means illustrated above and described and system provide multiple wavelength or sequence is applied.

In general, system of the invention includes guidance system, to ensure the complete and comprehensive treatment by light stimulus.It can incite somebody to action By fixed target, follow-up mechanism forms and the fixation/tracking/register system linked with system operatio is included in the present invention.

In specific preferred embodiment, the geometrical pattern of sequence offsets while laser facula, to realize melting for target tissue It closes and completely treats.This is by the way that once side arranges that multiple hot spots are executed in a manner of time-saving on the target tissue.This Array is sequentially scanned, deviated or is redirected the pattern of hot spot as a whole simultaneously, entire to cover during single therapy Target tissue.

This can be executed in a controlled manner by using optical scanner mechanism 40.Fig. 5 and Fig. 6 is shown can be with the shape of MEMS mirror The optical scanner mechanism 40 that formula uses, with substrate 42, which has electronically actuated controller 44 and 46, when to the electricity When the controller of son actuating applies and removes electricity, the electronically actuated controller is to tilt and mobile mirror 48.To controller 44 and 46 application electricity keep mirror 48 mobile, thus pattern phase while make the laser facula reflected on it or other geometric objects It should be moved on the target tissue of patient.This for example can adjust optical scanner mechanism by using electronic software program (program) 40 until target tissue is completely covered or at least part of target tissue in need for the treatment of is exposed to phototherapy in an automated way It executes.The optical scanner mechanism can be also small beam diameter scanning galvanometer system or similar system, such as by Thorlabs company The system of distribution.Such system can be with required modes of deflection scanning laser.

By parameter of the invention determine applied radiation energy or laser be not it is destructive or damaging, The geometrical pattern of laser facula can be for example overlapped, without destroying tissue or forming any permanent damage.But, specific Preferred embodiment in, as shown in Figure 7, the pattern of hot spot is in irradiation hour offset every time, thus the shape between preceding once irradiating At interval, to allow to radiate and prevent the possibility of thermal damage or histologic lesion.Therefore, as shown in Figure 7, example is shown as 16 The pattern of the grid of hot spot irradiates hour offset every time, so that the laser facula occupies the space different from previous exposure.It should manage Solution, the signal of circle or hollow dots and solid dot is using being only illustrative purpose, to illustrate that spot pattern is to area according to the present invention The previous and subsequent attack in domain.The spacing of laser facula prevents from making tissue overheating and damage.It should be appreciated that this occurs to entire target Tissue has received phototherapy or until reaching required effect.This can for example be executed by scan mechanism, such as pass through Xiang Weijia Work mirror applies electrostatic torque, as shown in figs. 5 and 6.It is (anti-by the way that the small laser facula separated by no irradiation area is used in combination Only heat accumulation) there is the grids of a large amount of hot spots with every side, extremely fast with no damage and invisibly with short irradiation duration It is feasible for treating big target area.

By the redirection for rapidly and sequentially repeating entire while application the grid array of hot spot or geometric object Or offset, the complete covering of target tissue (such as retina of people) can be fast implemented, without hot tissue damage.Join according to laser Several and required application can determine this offset by algorithm, with ensure most fast treatment time and because heat tissue caused by minimal damage Risk.

For example, below by Fraunhofer approximate (Fraunhoffer Approximation) modeling is used.It utilizes The exposure mask of 9x9 grid, 9 microns of aperture radius, 600 microns of small pitch of holes, using 890 nm wavelength lasers, 75 millimeters Exposure mask-lens separation and 2.5 millimeters x2.5 millimeters of second level mask dimensions, parameter below will generate the light with 6 microns The grid of 19 hot spots in every side at 133 microns of the interval of spot size radius.Given desired zone side length " A ", give it is each rectangular Interval " R ", spot radius " r " between the output pattern hot spot " n " on side, hot spot and to rectangular side length needed for treatment region " A ", irradiation number " m " needed for treatment can be given by the following formula (covering of fusion small light spot application):

By above-mentioned setting, the number of operations m for needing to treat different irradiation places can be calculated.For example, being conducive to the 3 for the treatment of X3 millimeters of regions of millimeter will need 98 offset operations, need about 30 seconds treatment times.Another example is 3 centimetres x3 centimetres Region.For such big treatment region, 25 millimeters x25 millimeters of biggish second level mask dimensions can be used, to generate The treatment grid of 190, every side hot spot at 133 microns of the interval with 6 microns of spot size radiuses.Due to the second level exposure mask Size and the identical multiple of required treatment area increase, thus about 98 offset operation number and therefore treatment in about 30 seconds when Between be constant.3 millimeters of field size for example will allow to treat the macula lutea of entire people in single fraction irradiation, be conducive to common blinding The treatment of situation such as diabetic macular edema and age-related macular degeneration.Executing 98 times whole sequence offsets will ensure that Macula lutea is completely covered.

Certainly, the number of generated hot spot and bulk yielding and changeable in pattern array at the same time, thus according to given The Treatment need of application can easily adjust the number for completing the required sequence offsets operation for the treatment of.

Moreover, quantum mechanics behavior can be observed by aperture employed in diffraction grating or exposure mask, allow laser The Arbitrary distribution of input energy.This will allow to generate random geometry or pattern, such as in lattice, line or any other Multiple hot spots of required pattern.The other methods for generating geometry or pattern can also be used in the present invention, such as using more A optical fiber or lenticule.

Referring now to Fig. 8 and Fig. 9, using the geometrical pattern of small laser facula, the present invention considers to use other several substitution What object or figure.For example, single laser line 50 that is continuous or being formed by a series of close hot spot of spacing can be created.It can make With off-set optical scan mechanism in the overlying regions sequential scan line, as shown in arrow downward in Fig. 8.Referring now to Fig. 9, The identical geometric object of rotatable line 50, as shown by arrows, to create round phototherapy field.But, the method is potential negative Influence is that central area will be repeated irradiation, thereby increases and it is possible to reach unacceptable temperature.But, by increase irradiation between when Between or form gap in the line and can overcome this disadvantage to not irradiating central area.

Power limit in current micropulse diode laser requires quite long irradiation duration.Irradiation time Longer, center-hot spot heat-sinking capability towards the not illuminated tissue at the edge for being located at laser facula is more important.Therefore, 810 The micropulse laser light beam of nanotube diode laser should have 500 milliseconds or a smaller irradiation envelope duration, and compared with About 300 milliseconds goodly.Certainly, if micropulse diode laser becomes more high-power, when should accordingly reduce irradiation persistently Between.

In addition to power limit, another parameter of the invention is the frequency or continuous impulse of duty ratio or micropulse column Between thermal relaxation time length.It has been found that using the scarcely perceptible pulse conveyed through adjusting in the similar irradiation level of similar MPE level 10% duty ratio of impulse light or the significant risk for increasing lethal cellular damage of more high duty ratio.But, less than 10% and Preferably 5% or smaller duty ratio show to rise and control in the horizontal enough heat of the MPE cell responded to stimulating organism It treats, but keeps below the expected level for generating lethal cellular damage.But, duty ratio is lower, and the irradiation envelope duration increases Add, and in some cases can be more than 500 milliseconds.

Each micropulse continues part millisecond, and the duration is usually in 50 microseconds between 100 microseconds.Therefore, right In 300 to 500 milliseconds of irradiation envelope duration, and the duty ratio less than 5%, there is the plenty of time between micropulse to permit Perhaps the thermal relaxation time between continuous impulse.In general, needing the thermal relaxation time between 1 and 3 millisecond between successive pulses Delay, be preferably about 2 milliseconds.For sufficient treatment, cell usually by the laser irradiation between 50 to 200 times or is hit It hits, and preferably in each position between 75 to 150.In the case where having 1 to 3 millisecond of relaxation or interval time, according to It is average 200 according to the total time of above-described embodiment treatment given area (or the position for being especially exposed to the target tissue of laser facula) Between millisecond and 500 milliseconds.Thermal relaxation time is needed, in order to avoid overheating the cell in the position or in hot spot, and is prevented Cell is damaged or destroys.

Inventor is it has been found that according to the present invention to age-related macular degeneration (age-related macular degeneration；AMD the treatment of patient) can slow down progress or even prevent the progress of AMD.This restorative therapeutic effect Further evidence is that inventor has found that treatment can be reduced uniquely because of choroidal neovascularization (choroidal Neovascularization the risk of the visual loss in AMD caused by) is up to 90%.After treatment according to the present invention, Most patients have seen that logMAR visual acuity and the comparison significant improvement of visual acuity among dynamic function, some experience more preferably Eyesight.It is believed that this is made by the function of targeting, holding and " normalization " (tending to normal) retinal pigment epithelium (RPE) With.

Although systemic diabetes persistently exist, it is also proved treatment prevention or reverting diabetes view according to the present invention The performance of retinopathy morbid state, without with treatment-related damage or ill-effect.Inventor's research shows that treatment Restorative effect the risk of the progress of diabetic retinopathy uniquely can be reduced by 85%.On this basis, it is assumed that this Invention may be restored by inducing in the RPE cell influenced by diabetes to more normal cell function and cytokine-expressing It acts on, similar to clicking " resetting " button of electronic device to restore factory default setting.

Based on information and research above, SDM treatment can directly affect target tissue especially retinal pigment epithelium (RPE) layer In cytokine-expressing and heat shock protein (HSP) activation.Inventor is it is mentioned that full retina and full macula lutea SDM are reduced The progression rates of many retinal diseases, including serious non-proliferative and proliferative diabetic retinopathy, AMD, DME Deng.When necessary, the treatment benefit in the personal known treatment with these retinal diseases combines no known bad Therapeutic effect, allow consider early stage and it is preventative treatment, freely apply and treat again.The replacement theory also indicates that this Invention can be applied to many different types of RPE and mediate retinal disease.In fact, inventor is recently it has been found that full macula lutea is controlled Treatment, which can dramatically, improves Local Electroretinogram, retinal pigment degeneration, cone bar retinosis and this special format Retinal function and health, view in sick (Stargardt ' s disease) (previously having found no other treatments to do so) Film susceptibility and dynamic logMAR visual acuity and comparison visual acuity.

Currently, the management of chronic progressive retinal disease is instructed in retina image-forming and visual acuity test.Due to tissue and/ Or organ structure damage and visual loss are terminal illness performances, therefore the treatment started at this moment must be strengthened, usually It is extended and expensive, and cannot usually improve visual acuity and seldom restore twenty-twenty vision.If due to be proved the present invention for Dry retinal disease is effective treatment without bad therapeutic effect, and due to its safety and efficacy, usually be can be used It treats morbidity or symptom or as such retinal disease of the eyes prophylactically to prevent or postpone retinal disease Prophylactic treatment.Improve retinal function and therefore improve health it is any treatment should also be as reduction disease severity, progress, Adverse events and visual loss.By starting to treat ahead of time before pathologic structure changes, and pass through conventional function guidance Again the benefit to keep treatment is treated, therefore structural degeneration and visual loss may be delayed by (if if being not blocked from).Even if The rate of progression of disease may also lead to the long-term significant reduction of the complication of visual loss in decline less big in early days.By subtracting The consequence of light major defect, can reduce disease journey, slow down progress, and reduce complication and visual loss.This is reflected in inventor Research in, discovery treatment by the progress of diabetic retinopathy and the risk of visual loss reduce by 85% and by AMD into The risk of exhibition and visual loss reduces by 80%.

One embodiment according to the present invention determines that the eyes of patient such as patient have the risk of disease.This can at As abnormal detectable execution before.Such determination can be by finding out whether patient has the risk of chronic progressive disease, example Such as retinopathy, including diabetes, the risk of age-related macular degeneration or retinal pigment degeneration is reached.As replacing In generation, is additional, and the inspection of patient or the result of test may be abnormal.Executable specific test such as physiology test or gene are surveyed Examination, to confirm that patient has the risk of disease.

When view of the treatment or prevention property protection with chronic progressive disease or the risk with chronic progressive disease When film or other eye tissues, generate sub- lethal and the solidifying laser light of true subthreshold value light is created in retinal tissue Beam, and at least part of retinal tissue is exposed to laser beam generated, without damage the exposure retina or Central fovea tissue, to provide the preventative and protectiveness treatment of the retinal tissue of eyes.Treated retina may include Central fovea, the small recessed, retinal pigment epithelium (RPE) in center, choroid, choroidal neovascularization, subretinal fluid, Huang Spot, macular edema, other central fovea and/or central fovea peripheral region.The laser beam can be irradiated in only one of retina Point, or substantially entire retina and central fovea.

Although most of therapeutic effects seemingly long-term (if not permanent), clinical observation show that it seems once in a while It disappears.Correspondingly, tissue is periodically treated again.This can according to formulation plan or ought for example pass through the view of periodic monitoring patient Feel and/or retinal function or situation determine execution when the tissue needs of patient are treated again.

Although present invention is particularly suitable for the treatment of retinal disease, such as diabetic retinopathy and macular edema, It has been found that Other diseases can also be used for for it.System and method of the invention can be by trabecular network (trabecular mesh) conduct The target for treating glaucoma customizes treatment field template by another kind and realizes.Moreover, to the eye for suffering from advanced open-angle glaucoma Optic nerve has been displayed using SDM treatment retinal tissue (as described above) for eyeball and the improved key of gangliocyte function refers to Mark indicates the significant Neuroprotective effect of this treatment.The visual field also improves, and without bad therapeutic effect.It is therefore believed that foundation SDM of the present invention can be independently of intraocular pressure (intraocular pressure；IOP the risk by reducing visual loss is reduced) come auxiliary Help the clinical management of glaucoma.

As described in detail above, it has therefore proved that low-intensity/high density subthreshold value (sub- lethal) diode micropulse laser device (SDM) traditional retinal laser indication such as diabetic macular edema, proliferative diabetic retinopathy, center are being treated Property slurry type chorioretinopathy and branch retinal vein occlusion remaining be it is effective, without bad therapeutic effect.As above It is described, the mechanism of retinal laser therapy is known as " resetting to default (reset to default) " theory sometimes herein, It assumes that the Main Patterns of retinal laser effect are the sub- lethal activation of retinal pigment epithelium (RPE) heat shock protein.

The research that inventor executes recently also indicates that SDM should be neuroprotective in open-angle glaucoma.It is linear It is maximum that regression analysis shows that value most abnormal before the treatment is improved after being treated for nearly all measure.According to this hair It is bright, to advanced open-angle glaucoma (open-angle glaucoma；OAG the full macula lutea SDM of eyes), which is treated, to be improved The key index of optic nerve and gangliocyte function indicates significant neuroprotective and effectively treats.The visual field also improves, and does not have There is bad therapeutic effect.Therefore, it generates the micropulse laser light beam with above-mentioned characteristic and parameter and applies the laser beam In the eyes with glaucoma or the risk with glaucoma retina and/or central fovea tissue to being exposed to the laser beam Retina and/or central fovea tissue generate therapeutic effect, without destroying or permanent damage retina and/or central fovea group It knits, and also improves the optic nerve of eyes and/or the function or situation of retinal ganglial cells.

The health and function effect of retinal ganglial cells and optic nerve by retinal pigment epithelium (RPE).Retina Stable state is mainly via the referred to as still indigestion of the little albumen secreted from RPE into intercellular space of " cell factor " but pole Its complicated interaction is maintained by RPE.The some RPE derived cell factor such as pigment epidermal derived factors (pigment epithelial derived factor；It PEDF) is neuroprotective.RPE cell factor can be changed in retinal laser therapy Expression including but not limited to increases the expression of PEDF.According to the present invention, in the case where no retinal damage, the effect of SDM It is " with supporting ", retinal function is made to tend to normal.By normalization RPE function, thus retina automatic adjustment and cell because Sublist, which reaches, to be also normalized.This shows that the normalization of retina cell's factor expression may be the Neuroprotective effect of SDM in OAG Root.

Although SDM has the function of chronic progressive retinal disease significant beneficial, these most of diseases do not have Other treatments for having any benefit.In this regard, retina CPD is also similar to the CPD in other places.Include type-2 diabetes mellitus, In all CPD of Alzheimer disease, idiopathic pulmonary fibrosis (IPF) and ischemic heart disease and various Myocardial damages, It identifies the exception of HSP system and finds that stimulation is beneficial.Currently, in addition to the present invention, being pierced without any non-physical treatment The HSP in systematicness CPD is swashed with the effect of supporting.With disease of eye it is associated SDM's experience have shown that, suitably designed PEMR should Treat effectively and safely any CPD for influencing any other part of body.Moreover, the retina that can not be treated in script SDM in disease experience have shown that, the beneficial effect of PEMR elsewhere should be important rather than inappreciable, steady , it is significant and safe.As SDM, PEMR to the effect of the CPD in places other in body will be likely to that disease cannot be cured The main reason for sick (age, diabetes, genetic defect etc.), on the contrary, effect will be by repairing because of principal disease development of defects Exception slow down, prevent or reverse disease process.By periodically treating maintenance therapy benefit again, the process of lysis is answered When being weakened, to reduce dead and disabled risk.

Since heat shock protein plays a role in terms of responding a large amount of unusual conditions in the bodily tissue other than ocular tissue, It is believed that similar system and method can be advantageously used in treatment such unusual condition, infection etc..So the present invention It is related to the control application of impulse ultrasound or electromagnetic radiation, to treat unusual condition, including inflammation, auto immune conditions, Yi Jitong Cross the fibre optics and the come-at-able cancer of focused electromagnetic/sound wave of endoscope or surface-probe.For example, with maximum transfer Cancer on the surface of the prostate of threat can be close by the fibre optics in proctoscope.Colon tumor can pass through fibre system It is close, those of as used in colonoscopy.

As it appears from the above, small fault folding of subthreshold value diode pulse laser (SDM) light stimulus in stimulation ocular tissue It is effective in terms of the direct reparation of folded albumen.In addition to HSP activation, this another way that may occur is because of hot time-histories Temperature peak caused by the micropulse of form allows water to spread in active site of protein, and this allows that albumen is prevented to restore its nature The fracture of peptide-peptide hydrogen bond.The magnitude that diffusion of the water into albumen causes the quantity for inhibiting hydrogen bond to increase by 1,000 times.Therefore, phase Believe that this process can also be advantageously applied to Other diseases.

Laser therapy can induce HSP and generate or activate and change cytokine-expressing.Non-lethality cellular stress (such as swash Light radiation) it is more unexpected and serious, HSP activation is quicker and steady.Therefore, very high by having for each SDM irradiation generation The burst of repetition low temperature thermal spike of rate of change (every the micropulse of 100 microsecond increase about 7 DEG C or 70,000 DEG C/sec) piercing Swash HSP activation in terms of it is especially effective, especially compare with continuous wave laser carries out subthreshold value treatment non-lethality irradiate (its only Reproducible harmonic(-)mean tissue temperature rise).

System and method according to the present invention, impulsive energy source such as laser, ultrasound, ultraviolet light, radio frequency, microwave radio etc. With energy parameter, which is selected to cause hot time-histories in tissue or body fluid, thus will during short time period The target tissue or rehydration temperature are increased to enough levels, to obtain therapeutic effect, while keeping flat during long period Equal tissue temperature is lower than predeterminated level, to avoid permanent tissue damage.It is believed that the creation of the hot time-histories stimulates heat shock protein Activation generates and promotes albumen reparation without causing any cellular damage.The parameter of the impulsive energy source and its to the target group It knits or the application of target body liquid is important for creating the hot time-histories, damaged with obtaining therapeutic effect without causing.

These parameters selection can by require for HSP activation Arrhenius (Arrhenius) integral be greater than 1 or One determines.Arrhenius integral is for analyzing the influence of the effect to biological tissue.See, for example, The CRC Handbook Of Thermal Engineering (the hot engineering manual of CRC), Frank Kreith is edited, Springer Science and Business Media (Springer Verlag science and sponsored media) (2000).Meanwhile selected parameter must not the permanent damage group It knits.Therefore, the Arrhenius integral for damage also can be used, wherein the Arrhenius solved is integrated less than 1 or one.

Alternatively, in terms of meeting the energy deposition and temperature rise that measured per unit gram during several minutes of period is organized FDA/FCC limitation, to avoid permanent tissue damage.The FDA/FCC of energy deposition and temperature rise is required to be widely used and can Such as in www.fda.gov/medicaldevices/deviceregulationandguidance/g uidancedocumen Ts/ucm073817.htm#attacha for electromagnetic sources, and Anastosio and P.LaRivero, Emerging Imaging Technologies (emerging imaging techniques) the .CRC Press (2012) of editor, For ultrasound sources (being used for supersonic source) is referred to.

In general, the tissue temperature rise within short time period (such as several seconds or part second) between 6 DEG C and 11 DEG C Therapeutic effect for example can be formed by activation heat shock protein, but during long period (such as several minutes (such as 6 points Clock) during) keep average tissue temperature will lower than predetermined temperature (such as 6 DEG C and even 1 DEG C or lower under specific circumstances) It will not permanent damage tissue.

As described above, the energy source that will be applied in target tissue, which will have, must be determined and be selected therapeutic to obtain Effect simultaneously will not permanent damage tissue energy and operating parameter.Such as in the feelings using beam energy source such as laser beam Under condition, it is necessary to consider optical maser wavelength, duty ratio and overall pulse column duration parameters.It is contemplated that other parameters include laser The radius and average laser power in source.At least one other parameter can be influenced by one of adjusting or selecting these parameters.

Figure 10 and Figure 11, which is shown, compares laser source radius (between 0.1 centimetre and 0.4 centimetre) and spike train duration (between 0.1 and 0.6 second) by watt as unit of mean power figure.Figure 10 shows 880 nanometers of wavelength, and Figure 11 has There is 1000 nanometers of wavelength.It can be seen that, in the drawings, when required power reduces, continues with total column with the radius in source Between increase and with wavelength reduce and monotonously reduce.The preferred parameter of the radius of laser source is 1 millimeter to 4 millimeters.For 880 nanometers of wavelength, in the case where the radius of laser source is 1 millimeter and the overall pulse duration is 600 milliseconds, minimum power Value is 0.55 watt.When laser source radius is 4 millimeters and the overall pulse column duration is 100 milliseconds, for 880 nano wave lengths Maximum power value is 52.6 watts.But, when laser of the selection with 1000 nanometers of wavelength, in the laser source with 1 millimeter Radius and in the case where 600 milliseconds of overall pulse column duration, minimal power values are 0.77 watt, and when laser source radius is When 4 millimeters and overall pulse column duration are 100 milliseconds, maximum power value is 73.6 watts.Respective peaks during single pulse Value power is by obtaining mean power divided by duty ratio.

The volume for the tissue area to be heated by wavelength, linked groups absorption length and width of light beam determine.Always Pulse duration and average laser power determine the gross energy that tissue is heated through conveying, and the duty ratio of spike train provides phase The peak value of pass or peak power relevant to average laser power.Preferably, the energy parameter of impulsive energy source is chosen so that Target tissue per cubic centimeter absorbs about 20 to 40 joules of energy.

In thin melanin layer in retinal pigment epithelium, absorption length is very small.In the other parts of body, inhale Receiving length is not usually that youngest is small.In the wavelength changed in the range of from 400 nanometers to 2000 nanometer, penetration depth and skin In the range of 0.5 millimeter to 3.5 millimeters.Range of the penetration depth at 0.5 millimeter to 6.8 millimeters into human body mucous tissue It is interior.Correspondingly, heating volume will be limited to the outer or inner surface of setting radiation source, and depth is equal to penetration depth, and lateral dimension Equal to the lateral dimension of radiation source.Due to using the treatment of beam energy source in proximity or near the accessible surface in inside Illing tissue, therefore source radius between 1 millimeter to 4 millimeters and operate 880 nanometers of wavelength and generate about 2.5 millimeters and wear Saturating depth and 1000 nanometers of wavelength generate about 3.5 millimeters of penetration depth.

It has been determined that being, for example, less than 1 second in a short period of time, target tissue can be heated to up to about 11 DEG C to form this hair Bright therapeutic effect, while during such as several minutes of long period, target tissue mean temperature is held in lower temperature Range is, for example, less than 6 DEG C or even 1 DEG C or lower.Duty when the overall pulse column duration selection provide can radiate when Between be spaced.It has been found that in the case where the overall pulse duration is between 100 milliseconds and 600 milliseconds, less than 10% and preferably Duty ratio between 2.5% and 5% is effective.Figure 12 and Figure 13 is shown in a length of 880 nanometers and in Figure 13 of Figure 12 medium wave In the case where a length of 1000 nanometers of medium wave, there is the laser source of the radius between 0.1 centimetre and 0.4 centimetre to decay to from 10 DEG C 1 DEG C of time.It can be seen that, when using 880 nanometers of wavelength, die-away time is shorter, but two kinds of wavelength are all wanted acceptable Ask and range of operating parameters in, to obtain benefit of the invention without causing permanent tissue damage.

It has been found that during global radiation, at least 6 DEG C of the average temperature rising increase of required target region and up to 11 DEG C, and compared with HSP is caused to activate for about 10 DEG C goodly.The control of target tissue temperature is determined by selection source and target parameter, so as to activate for HSP Arrhenius integral be greater than 1, while ensuring compliance with conservative FDA/FCC and requiring to avoid damaging or damaging Arrehenius Integral is less than 1.

To meet conservative FDA/FCC limitation to avoid permanent tissue's damage, for light beam and other electromagnetic radiation sources, The average temperature rising of target tissue is 1 DEG C or smaller during any 6 minutes.Fig. 1 above 2 and the temperature of Figure 13 display heating target area are logical Cross thermal diffusion from about 10 DEG C of temperature rise be reduced to 1 DEG C needed for the typical attenuation time, as can be seen from Figure 12, when wavelength is 880 to receive Rice and source diameter be 1 millimeter when, temperature damping's time be 16 seconds.When source diameter is 4 millimeters, temperature damping's time is 107 seconds. As shown in Figure 13, when wavelength is 1000 nanometers, when source diameter is 1 millimeter, temperature damping's time is 18 seconds, works as source diameter When being 4 millimeters, temperature damping's time is 136 seconds.This keeps flat completely during the process of several minutes (such as 6 minutes or shorter) In the time of equal temperature rise.Although during applying energy source to tissue, soon (such as within part second) by target tissue Temperature increase for example to about 10 DEG C, but lower duty ratio provides longer time between the energy pulse for being applied to tissue Section and shorter spike train duration ensure the abundance in the shorter time period for including several minutes (such as 6 minutes or shorter) Temperature diffusion and decaying, damaged from without permanent tissue.

The parameter of each energy source (including microwave, infrared laser, radio frequency and ultrasound) is different, because being directed to these inhomogeneities The absorption properties of the energy source of type, tissue are different.Tissue water content can be different because of organization type, but, normal or connect Under the conditions of close normal, the consistency of the attribute of tissue can be observed, to allow open organizational parameter, they are by clinician It is widely used in design treatment.It is shown in the table of the attribute of the electromagnetic wave in biological medium below, table 1 is related to High water cut Muscle, skin and the tissue and table 2 of amount are related to having the fat of low water content, bone and tissue.

The attribute of electromagnetic wave in 1 biological medium of table: muscle, skin and tissue with high-moisture

The attribute of electromagnetic wave in 2 biological medium of table: fat, bone and tissue with low water content

It is long that the absorption length of radio frequency in bodily tissue compares body sizes.Therefore, heating zone is by as RF energy The size of the coil in source determines, rather than is determined by absorption length.In the long range r enclosed offline, (close) magnetic field of coil is with 1/ r³Speed decline.In lesser distance, electric field and magnetic field can be indicated with vector potential, the vector potential accordingly can be used first and The ellptic integral of second class is indicated with closing form.Heating occur only at dimensionally with the comparable area of the size in coil source itself Domain.Correspondingly, the region characterized by radius is if desired preferentially heated, then source coil will be selected to have similar half Diameter.Due to the 1/r in magnetic field³Decline, outside the hemispherical area of radius, heating decline is quickly.Due to suggesting using only can be from outer Portion or from inner cavity close to the radio frequency of illing tissue, therefore reasonable consideration coil radius is between about 2 to 6 millimeters.

The radius and the ampere-turn in source coil of source coil provide the amplitude and spatial dimension in magnetic field, and radio frequency be by The amplitude of electric field and the associated factor of the amplitude in magnetic field.Heating be with conductivity and electric field square product it is proportional.For Interest target tissue outside or near inner surface, conductivity are the conductivity of skin and mucous tissue.The duty ratio of spike train with And total column duration of spike train is the factor for influencing how many gross energy and being fed to tissue.

The preferred parameter of source of radio frequency energy be determined to be in coil radius between 2 and 6 millimeters, 3 to 6MHz model Radio frequency, 0.2 to 0.4 second overall pulse column duration in enclosing, and the duty ratio between 2.5% and 5%.Figure 14 extremely schemes How the number of 17 display ampere-turns changes with these Parameters variations, is directed to HSP activation generation about 1 or one to provide The temperature rise of Arrhenius integral.Figure 14 is please referred to, the RF frequency of 6MHz, the spike train between 0.2 second and 0.4 second are held The continuous time, the coil radius between 0.2 and 0.6 centimetre and 5% duty ratio, peak ampere the number of turns (NI) is at 0.6 centimetre Coil radius is 13 and is 20 in 0.2 cm coil radius.For 3MHz frequency, as shown in Figure 15, when spike train continues Between for 0.4 second and coil radius is 0.6 centimetre and when duty ratio is 5%, peak ampere the number of turns is 26.But, for identical 5% duty ratio, when coil radius is 0.2 centimetre and the spike train duration is 0.2 second, peak ampere the number of turns is 40.Scheming 2.5% duty ratio is used in 16 and Figure 17.As shown in Figure 16, for having 0.6 centimetre of coil radius and 0.4 second arteries and veins The 6MHz radio frequency of punching column duration generates 18 ampere-turns, and when coil radius is only 0.2 centimetre and spike train continues Between be 0.2 second when, generate 29 ampere-turns.Figure 17 is please referred to, in the case where the 2.5% duty when radio frequency of 3MHz, when When the spike train duration is 0.4 second and coil radius is 0.6 centimetre, peak ampere the number of turns is 36, and when spike train continues It is 57 ampere-turns when time is 0.2 second and coil radius is 0.2 centimetre.

Figure 18 shows that, for the coil radius between 0.2 centimetre and 0.6 centimetre, temperature rise is from about for source of radio frequency energy 10 DEG C decay to about 1 DEG C of time (in seconds).When radio-frequency coil radius is 0.2 centimetre, temperature damping is about the time 37 seconds, and when radio-frequency coil radius is 0.5 centimetre, temperature damping is about 233 seconds the time.When radio-frequency coil radius is 0.6 li Meter Shi, die-away time is about 336 seconds, still within acceptable die-away time, but in the upper limit of the range.

Microwave is workable another electromagnetic energy source according to the present invention.The frequency of microwave determines tissue penetration distance. It is big that microwave wavelength is compared in the gain of tapered microwave horns, and in these cases, energy master is to be radiated in narrow forward direction for mark In load.In general, microwave source used according to the present invention has centimetre or the linear dimension of smaller magnitude, therefore the source is less than The microwave source can be approximately in the case dipole antenna by wavelength.Such small microwave source is easier to be inserted into inner body cavity simultaneously And radiation outer surface can also be used to.It in the case, can be approximately hemisphere by heating zone, radius is equal to treated body The absorption length of microwave in body tissue.When using micro-wave therapeutic in outer surface or can be from the tissue near the close surface in inner cavity When, use the frequency within the scope of 10 to 20GHz, wherein corresponding penetration range is only between about 2 and 4 millimeters.

It is determined using the temperature rise of the tissue of source of microwave energy by the mean power and overall pulse column duration of microwave.Pulse The duty ratio of column determines the peak power of the single pulse in spike train.When the radius using the source less than about 1 centimetre, and usually When using frequency between 10 and 20GHz, preferably 0.2 and 0.6 second spike train duration.

Required power increases with the column duration and monotonously reduces as microwave frequency increases.For 10GHz Frequency, when the spike train duration be 0.6 second when, mean power be 18 watts, and when the spike train duration be 0.2 second When, mean power is 52 watts.For 20GHz microwave frequency, when pulse is classified as 0.6 second, using 8 watts of mean power, and When the spike train duration being only 0.2 second, mean power can be 26 watts.Corresponding peaks power is simply by by mean power It is obtained divided by duty ratio.

Referring now to Figure 19, frequency of the graphical display with 10GHz and the spike train between 0.2 second and 0.6 second The microwave of duration averaged microwave power (by watt as unit of).Figure 20 is similar pattern, but is shown for 20GHz's The averaged microwave power of the microwave of frequency.Therefore it will be seen that averaged microwave source power is with total column duration and microwave frequency Change and changes.But, control condition is the Arrhenius integral about 1 for the HSP activation in heating zone.

Referring to figure 2. 1, graphical display compares the microwave frequency between 58MHz and 20000MHz, and temperature declines from about 10 DEG C Reduce to 1 DEG C of time (in seconds).Minimum and maximum temperature decaying for preferred microwave frequency range are to work as Microwave Frequency It is 8 seconds when rate is 20GHz, and when microwave frequency is 10GHz is 16 seconds.

Using ultrasound as energy source can tissue with different depths in heating surface tissue and body, including Quite deep tissue.The absorption length of ultrasound in body is considerably long, proves as it is widely used in imaging.Correspondingly, may be used By focus ultrasonic in the target area of body deep within the body, the heating of focused sound beam focuses primarily upon the near cylindrical focus of the beam Area.The volume of heating zone is determined by the focal waist of Airy (airy disc) and the length of focus lumbar region, that is, confocal ginseng Number.Multiple beams in the source from different angle can also be used, heating betides the focal area of overlapping.

For ultrasound, when the Focus length and diameter of given ultrasonic transducer, for determining the related ginseng of tissue temperature Number is frequency, total column duration and the transducer power of ultrasound.Frequency, Focus length and diameter determine ultrasonic energy The volume of the focal area of concentration.Focal volume includes the target volume for treating tissue.With about 5 centimetres of diameters and about 10 centimetres The energy converter of Focus length be readily available.When supersonic frequency is between 1 and 5MHz and total column duration is 0.1 to 0.5 When the second, advantageous focal spot size is obtained.For example, Focus length and 5 centimetres of transducer diameter for 10 centimetres, focus body Product is 0.02 cubic centimetre in 5MHz and is 2.36 cubic centimetres in 1MHz.

Referring now to Figure 22, graphical display be averaged source power (by watt as unit of) compare frequency (1MHz and 5MHz it Between) and the spike train duration (between 0.1 and 0.5 second).It is assumed that 10 centimetres of energy transducer focus length and 5 centimetres of source Diameter.Power needed for providing the about 1 Arrhenius integral for HSP activation is held with frequency increase and with total column The continuous time increases and monotonously reduces.Given preferred parameter, for the minimum of 1GHz frequency and 0.5 second spike train duration Power is 5.72 watts, and for 1GHz frequency and 0.1 second spike train duration, maximum power is 28.6 watts.For 5GHz Frequency needed 0.046 watt for 0.5 second spike train duration, wherein 0.1 second spike train duration was needed 0.23 watt.Corresponding peaks power during single pulse divided by duty ratio simply by obtaining.

Figure 23 shows that temperature spreads from 10 DEG C or decays to 6 DEG C of time (with the second when supersonic frequency is between 1 and 5MHz For unit).Figure 24, which is shown, decays to the supersonic frequency from 1 to 5MHz from about 10 DEG C 1 DEG C of time (in seconds).It is right In 10 centimetres of preferred focus length and 5 centimetres of transducer diameter, when supersonic frequency is 1MHz, when maximum temperature is decayed Between be 366 seconds, and when microwave frequency be 5MHz when, minimum temperature decays to 15 seconds.For several minutes of testing time, work as FDA When requiring nothing more than temperature rise less than 6 DEG C, it is allowed in 366 second die-away time of 1MHz in the temperature rise that several minutes of periods reach 1 DEG C.From Figure 23 and Figure 24 can be seen that temperature rise of the die-away time than 1 DEG C of 6 DEG C of temperature rise is about 70 times small.

Figure 25 shows that the volume for comparing the focus heating zone of the supersonic frequency between 1 and 5MHz (is single with cubic centimetre Position).Consider 1 to the supersonic frequency between 5MHz, for these frequencies corresponding focal spot size in the milli from 3.7 millimeters to 0.6 Change in the range of rice, and the length of focal area changes in the range of from 5.6 centimetres to 1.2 centimetre.Corresponding treatment volume exists Change between about 2.4 cubic centimetres to 0.02 cubic centimetre.

Required HSP activation Arrhenius integral is provided to be greater than 1 and damage the example of parameter of the Arrhenius integral less than 1 It is total ultrasonic power between 5.8 to 17 watts, 0.5 second pulse duration, the interval between pulse in 5 seconds, at 50 seconds The overall pulse stream time in have overall pulse number 10.It will be about 1 millimeter of one side that target, which treats volume,.By with multiple while application The multiple ultrasounds of column application that are adjacent but separating and have spacing, can treat big with the ultrasonic system of similar laser diffraction optical system Treat volume.Multiple focused sound beam converges in body on very small therapeutic target, which allows minimum heating, removes Other than the overlapping bundles of rays at the target.This region will be heated and stimulate the activation of HSP and be promoted by transient high temperature peak value Into albumen reparation.But, the smaller area for giving pulse aspect of the invention and being treated in any given time, the treatment Meet the FDA/FCC requirement of long-term (several minutes) average temperature rising < 1k.The present invention and the existing treatment for pain and pulled muscle Property an important difference heating to treat be in the prior art without high T peak value, and these are effective activation HSP and promote albumen It repairs to be provided needed for curing in cell level.

For remedial HSP is activated and albumen is promoted to repair, spike train energy transport model is with respect to single pulse or gradually There is clear advantage into energy transport model.There are two considerations to constitute this advantage:

Firstly, a big advantage of HSP activation and albumen reparation in PEMR energy transport model is from the amount for generating 10 DEG C The peak temperature of grade.So big temperature rise has a significant impact to Arrhenius integral tool, what which quantitatively illustrated to be activated The number of HSP and the water of promotion albumen reparation diffuse into the rate of albumen.This is because temperature, which is constituted, has enlarge-effect Index.

It is important that temperature rise will not be held in high level (10 DEG C or higher) for a long time, because just violating at several minutes like that Between during section average temperature rising be necessarily less than the FDA and FCC requirement of 1 DEG C (or 6 ° in the case where ultrasound).

SDM or other PEMR energy transport models are by advisably selecting power, burst length, pulse spacing and wait control The volume of the target area for the treatment of uniquely meets above-mentioned this two considerations.It is because temperature must be at a good pace that the volume for the treatment of region, which is included in, Decay from the high level of its 10 DEG C of magnitudes, so that it (is 6 for supersonic frequency that long-term average temperature rising, which is no more than long-term FDA/FCC limitation, DEG C and for electromagnetic radiation energy source be 1 DEG C or lower).

For the region with linear dimension L, the e times of the time it takes that decays is about L to peak temperature in the tissue²/ 16D, wherein D=0.00143cm²/ the second is typical thermal diffusion coefficient.For example, die-away time is about 0.4 if L=1 millimeters Second.Accordingly for 1 millimeter of region on one side, the column being made of 10 pulses, 0.5 second each duration, between pulse Between be divided into 5 seconds can be achieved needed for TRANSIENT HIGH TEMPERATURE liter, while still not exceeding 1 DEG C of average, long term temperature rise.This is below into one Step proves.

The limitation of heating volume is that RF electromagnetic radiation is a kind of good for treatment body deep zones not as good as ultrasound Selection the reason of.Long skin depth (penetration range) and lead to big heating volume along the Ohmic heating of skin depth, Thermal inertia, which does not allow to peak, is worth temperature to activate HSP and promote albumen reparation, does not allow fast temperature to decay also to meet The long-term FDA and FCC of average temperature rising are limited.

Ultrasound has been used to the region of Therapeutic heat body, to mitigate pain and pulled muscle.But, which does not have It follows agreement of the invention and does not have the temperature peak for the excitation for being responsible for HSP.

Then, consider one group of focused sound beam, align them that the target area of body deep within the body.To simplify mathematics, it is assumed that should A little beams are substituted by the supercentral single source with spherical surface shape for focusing on sphere.The absorption length of ultrasound can be suitable It is long.Following table 3 is shown in the typical absorption coefficient of the ultrasound of 1MHz.Absorption coefficient is generally proportionate with frequency.

The typical absorption coefficient of 1MHz ultrasound of the table 3 in bodily tissue

It is assumed that because the Geometrical change of incident radiation caused by focusing is leading because arbitrarily changing caused by decaying, in focal point The intensity of incident ultrasound at distance r can be written as by approximation:

I (r)=P/ (4 π r²) (1)

Wherein, P indicates total ultrasonic power.

Shortest pulse duration t at r_pThe temperature rise of end is then

dT(t_p)=P α t_p/(4πC_vr²) (2)

Wherein, α is absorption coefficient and C_vFor constant volume thermal capacitance.Such case continues to reaching r, here, t_pThermal diffusion it is long Degree becomes suitable with r, or reaches the diffraction limit of focus on light beam.For lesser r, temperature rise is substantially independent from r.For example, false It is scheduled on the lesser radial distance compared with the radial distance determined by thermal diffusion and reaches diffraction limit.Then

r_dif=(4Dt_p)^1/2 (3)

Wherein, D is thermal diffusion coefficient, and for r < r_dif, in t_pTemperature rise be

dT(r_dif,t_p)=3P α/(8 π C_vD), wherein r < r_dif (4)

Therefore, in end-of-pulsing, we can write for temperature rise:

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

When applying Green (Green) function for thermal diffusion type

G (r, t)=(4 Ω Dt)^-3/2exp[-r²/(4Dt)] (6)

This initial temperature is distributed, it has been found that be in the temperature dT (t) of the focus r=0 of time t

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=3P α/(8 π C_vD) (8)

Following formula provides the good approximation of formula (7):

dT(t)≈dT_o(t_p/t)^3/2 (9)

As shown in Figure 26, which is in target treatment region for dT (t)/dT_oFormula (7) compared with (9).Bottom is bent Line is the approximate representation of formula (9).

It can be assessed now by the temperature rise provided by formula (9) for the Arrhenius integral of N number of spike train.In this formula,

dT_N(t)=∑ dT (t-nt_I) (11)

Wherein, dT (t-nt_I) be formula (9) expression, t is by t-nt_ISubstitution and t_IIndicate the interval between pulse.

Arrhenius integral can by by integrating range be divided into temperature peak generation part and temperature peak do not deposit Part approximatively assess.Temperature peak contribution and can by the integral on temperature peak apply Laplce (Laplace) endpoint formula simplifies.In addition, the integral on the part that peak value is not present can be by paying attention to non-peak temperature rise Reach asymptotic value quickly to simplify, to obtain good approximation by being risen with the asymptotic value alternate variation time. When executing these approximations, formula (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) result from (N-n)^-3/2N on and and for for typical interest N harmonic number (N, 3/ 2) size)

This formula is very interesting compared with for the formula of the SDM applied to retina.In addition to for this three-dimensional convergent beams situation Effective peak interval reduces other than 3 times, and first item is very similar to the item of the contribution of the peak value in retina.Including dT_N (Nt_I) Section 2 much smaller than the item in the case of retina.Background temperature rise is suitable with peak value temperature rise in amplitude.But here in meeting In the case of focal beam, the small (t of background temperature rise_p/t_I)^3/2Ratio.This indicates to activation or generates HSP and promote albumen reparation Peak value contribution importance because the background temperature rise similar with the temperature rise under continuous ultrasound heating state with peak value contribute compared with It is insignificant.At the end of spike train in addition this low background temperature rise also by thermal diffusion quick disappearance.

Figure 27 and Figure 28 is shown for pulse duration t_p=0.5 second, pulse spacing t_I=10 seconds and overall pulse number N =10, the amplitude of the logarithm for the Arrhenius integral for activating or generating for damage and for HSP is with dT_oChange and changes. For pulse duration t_p=0.5 second, pulse spacing t_I=10 seconds, and total ultrasonic pulse number N=10, for damage and The logarithm of (formula 12) is integrated with the temperature rise dT from single pulse for the Arrhenius of HSP activation_o(as unit of degree Kelvin) Change and changes.Figure 27 is shown with Arrhenius constant A=8.71x10³³sec^-1And E=3.55x10^-12The damage of ergs Hurt the logarithm of integral.Figure 28 is shown with Arrhenius constant A=1.24x10²⁷sec^-1And E=2.66x10^-12Ergs's The logarithm of HSP activation integral.Being graphically displayed at until dT in Figure 27 and Figure 28_oMore than 11.3k, Ω_damageJust more than 1, and Ω_hsp1 is both greater than on shown entire section, this is to carry out cell repair without the condition needed for damaging.

α=0.1cm is worked as in formula (8) display^-1, the dTo of 11.5K is obtained by 5.8 watts of total ultrasonic powers.This is easy to reality It is existing.If α increases by 2 or 3 times, gained power is still easy to accomplish.The volume in the region of temperature rise is constant (it is, corresponding r=r_d =(4Dt_p)^1/2Volume) be 0.00064 cubic centimetre.This corresponds to the cube for 0.86 millimeter on one side.

The simply example proves that focusing ultrasound should can be used to stimulate repairing for body depths by the equipment being easy to get Renaturation HSP.

For the treatment for accelerating biggish internal volume, SAPRA system can be used.

Impulsive energy source can be guided to the outside of body, adjacent to target tissue or with close to the outside of the body The blood supply on surface.Alternatively, can into body cavity insertion apparatus, with to target tissue apply impulsive energy source.Energy source is applied It depends on selecting and making for treatment target tissue in the outside of body or the inside of body and using what type of device Energy source.

Light stimulus according to the present invention can be had by using endoscope (such as bronchoscope, proctoscope, Sigmoidoscope etc.) Effect is transmitted to the inner surface area or tissue of body.Various endoscopes are made of flexible pipe substantially, and the flexible pipe itself includes One or more inner tubes.In general, one of inner tube includes light pipe or multimode fibre, it is emerging to illuminate along endoscope leaded light Interesting region simultaneously enables a physician to see the object being located at by according to end.Another inner tube can be made of conducting wire, conducting wire conveying electricity Stream enables the surgeon to enough burn by according to tissue.Another inner tube can be made of biopsy tool, which enables a physician to cut And retain arbitrarily by according to tissue.

In the present invention, one of these inner tubes are used as electromagnetic radiation pipe, such as multimode fibre, to transmit SDM Or other pulse of electromagnetic radiation, it is fed into endoscope in the end that doctor is held.Referring now to Figure 29, photogenerated unit 10 (such as lasers with required wavelength and/or frequency) are generating electromagnetic radiation with controlled, pulse mode, such as swash Light is transported to the distal end (showing in Figure 30) of endoscope 54 by light pipe 52, which is inserted into body and this swashs Light or other radiation 56 are transported to target tissue 58 to be treated.

The photogenerated unit 10 of Figure 29 may include above with reference to photogenerated unit described in Fig. 1 to Fig. 6.But, conveying dress It sets or component may include endoscope, bronchoscope, make laser beam generated by light pipe 52.System may include that laser beam is thrown Shadow instrument or conveying device such as endoscope and observing system/camera will include two different components when in use.The observation system System/camera can provide feedback to display monitor, the display monitor may also include necessary computerized hardware, data input and Control, to operate Optical devices, transported laser or other impulsive energy sources and/or projection/observation assembly.Moreover, The pattern that can be deviated is produced, as described above.Certainly, the laser generation system of Fig. 1 to Fig. 6 is exemplary, and can be used other Apparatus and system generates laser or other pulsed electromagnetic radiation sources, it can be made operatively to pass through projector apparatus, such as scheme Endoscope shown in 29 and Figure 30 or light pipe etc..

The electromagnetic radiation of other forms, including ultraviolet waves, microwave, other rf waves are also produced and use, and pre- The long laser of standing wave.Moreover, also producing and using ultrasonic wave to create hot time-histories temperature peak in target tissue, it is enough Heat shock protein is activated or generated in the cell of target tissue without damaging target tissue itself.For this purpose, usually passing through instantaneous lifts target Tissue temperature (such as between 6 DEG C and 11 DEG C) long-term simultaneously (such as during several minutes) only 6 DEG C or 1 DEG C or smaller mode Impulse ultrasound or electromagnetic radiation energy source are provided and applied to target tissue.

For the deep tissue not near inner void, light pipe is not the effective means for conveying pulse energy.In this feelings Under condition, usable pulse low frequency electromagnetic energy or preferably impulse ultrasound in target tissue to cause series of temperature peak value.

Therefore, according to the present invention, apply impulse ultrasound or electromagnetic radiation source to target tissue or fluid, to stimulate HSP to generate Or it activates and promotes the albumen reparation in living animal tissue.In general, electromagnetic radiation can for ultraviolet waves, microwave, other penetrate Frequency wave, in laser of predetermined wavelength etc..On the other hand, if electromagnetic energy will be used for the deep tissue target far from natural hole, Then according to the depth of target tissue, wavelength is limited to the wavelength of microwave or rf wave by absorption length.But, for far from natural hole Deep tissue target, opposite long wavelength electromagnetic radiation is preferably ultrasonic.

Ultrasound or electromagnetic radiation create hot time-histories through chopping in the tissue, and stimulation HSP is generated or activated and promote Albumen reparation causes to damage without having to cell being treated and tissue.The area and/or volume of treated tissue also pass through It controls and minimizes so that temperature peak is in magnitude several times, for example, about 10 DEG C, while long-term temperature rise being kept to limit less than FDA regulation System, such as 1 DEG C.It has been found that organizing increased temperature can not enough sufficiently and quickly if treating too big tissue regions or volume Diffusion is to meet FDA requirement.But, the area for being treated tissue and/or volume and creation impulsive energy source are limited by adding Heat or in another way stress cell and tissue realize target that present invention stimulation HSP is activated or generated, while allowing quilt It treats cell and tissue dissipates in any waste heat to acceptable limitation generated.

It is believed that stimulation HSP generation can be effective to treat various tissue abnormalities according to the present invention, it is ailing, or even infection. For example, causing the main osculum for influencing nasal meatus and the respiratory epithelium in nasopharynx of the virus of flu.It is similar with retina, respiratory epithelium For thin, transparent tissue.Referring to figure 3. 1, show the cross-sectional view of head part 60, endoscope 54 is inserted into nasal cavity 62 and energy 56 are directed to tissue 58 to be treated in nasal cavity 62 such as laser.Tissue 58 to be treated can be located in nasal cavity 62, including Nasal meatus and nasopharynx.

It, can be by the infrared (infrared of wavelength regulation to water for the absorption for ensuring laser energy or other energy sources；IR) Absorption peak, or adjuvant dyestuff can be used to serve as photosensitizer.In this case, treatment will be then by following procedure group At: it drinks or part applies adjuvant, wait a few minutes so that adjuvant impermeable surface tissue, and followed by endoscope 54 Optical fiber provide laser or other energy sources more than 56 seconds to target tissue 58, as shown in Figure 31.To make patient comfort, can apply Local anesthetic is added to be inserted into endoscope 54 later.If desired, the process, such as one day or so can be repeated at periodic or other desired.

The treatment is by the activation for stimulating heat shock protein or generation and promotes albumen reparation, being treated thin without damaging Born of the same parents and tissue.As described above, it has been found that the lifting in the health of immune response and target cell and tissue of particular thermal shock protein It acts on.Energy source can be one-wavelength laser source, such as 810 nm wavelength lasers, with described in patents mentioned above application Similar mode provides, but is provided by endoscope etc., as shown in Figure 31.Adjuvant dyestuff is selected to increase laser absorption. Although this includes executing particular preferred approach and embodiment of the invention, it will be appreciated that according to the present invention, other classes can be used The energy and mode of movement of type are to realize identical target.

Referring now to Figure 32, for Other diseases, there are similar situations, wherein major target is the upper of upper respiratory trees Skin, in the part that diameter is greater than about 3.3 millimeters, it is, upper six generation of upper respiratory trees.Thin rete malpighii is by target epithelial cell It is separated with air flue chamber, is exactly in this layer, Ag-Ab reciprocation occurs, and virus such as flu and influenza virus is caused to be lost It is living.

Please continue to refer to Figure 32, the flexible light pipe 52 of bronchoscope 54 passes through 66 quilt of throat and tracheae by personal mouth 64 It is inserted into the bronchus 68 of respiratory trees.Herein, the tissue into this region of topmost portion provides simultaneously transmission laser or other Energy source 56, as above to treat the tissue and region about same way described in Figure 32.Consider the wave of laser or other energy The long IR absorption peak for being selected to the water that matching resides in mucus, with heat tissue and stimulate HSP to activate or generate and Promote albumen reparation, and with its additional benefit.

Referring now to Figure 33, Sigmoidoscope 54 its flexible light pipe 52 can be made to be inserted into anus and rectum 70 and enter large intestine 72 or Small intestine 74, to convey selected laser or other energy sources 56 to region to be treated and tissue, as shown in the figure.This can be used to help to control Treat colon cancer and other gastrointestinal problems.

In general, the process can be executed similar to colonoscopy, because to clear up all stool to intestines, patient can lie on one's side and cure Life can be thin by the length of Sigmoidoscope 54 light pipe portion 52 be inserted into rectum and it be moved to colon, large intestine 72 or small intestine 74 Region to be treated is reached in region.Doctor can observe the path of be inserted into flexible piece 52, or even observation position by monitor Tissue in the end of the Sigmoidoscope 54 of enteral, to observe region to be treated.By using other optical fiber or light pipe wherein it One, the end 76 of endoscope is directed to region to be treated, and laser or other radiation sources 56 will be pumped through Sigmoidoscope One of 54 light pipe, to treat the region of tissue, as described above, to organize 58 moderate stimulation HSP activation Or it generates.

Referring now to Figure 34, in another example, can will be present invention is advantageously employed in gastrointestinal tract, such as often claimed It is the situation in road stomach and intestine (GI) of mark with inflammation or the imbalance of other metabolic functions for " leakage intestines (leaky gut) " syndrome.By In similar with retina, gastrointestinal tract is easy by metabolic function offset influence, it is therefore contemplated that it will respond of the invention control well It treats.This can be executed by subthreshold value as described above, diode micropulse laser device (SDM) treatment, or by herein Other energy sources and device known in the art are addressed to execute.

Please continue to refer to Figure 34, the flexible light pipe 52 of endoscope etc. is inserted through throat and tracheae by the mouth 64 of patient Area 66 simultaneously enters in stomach 78, wherein tissue 58 to be treated is directed toward in its end 64, and laser or other energy sources 56 are directed to Tissue 58.Those skilled in the art will be appreciated that also can be used Sigmoidoscope and be inserted into across rectum 70 and enter stomach 78 or In any tissue between stomach and rectum.

If desired, chromophore pigment can be conveyed by taking orally to gastrointestinal tissue, radiation can be absorbed.For example, if will make For from unfocused 810 nm radiation of laser diode or LED, then the pigment will have absorption peak at 810 nanometers or nearby Value.Alternatively, can apply by the wavelength regulation of energy source to the slightly long wavelength of the absorption peak in water without outside Chromophore.

Present invention also contemplates that the capsule endoscope 80 that use example is as shown in Figure 35, to provide radiation and energy according to the present invention Amount source.Such capsule has lesser size, for example, about 1 inch long, so that patient swallows.As capsule or pill 80 are swallowed And enter in stomach and pass through gastrointestinal tract, when in place, capsule or pill 80 for example can receive power by antenna 82 And signal, so that activation energy source 84, such as laser diode and interlock circuit, suitable lens 86 focus laser generated Or radiation across radiolucent lid 88 and focuses on tissue to be treated.It should be appreciated that the position of capsule endoscope 80 can It determines by various modes, such as external imaging, signal trace, or even by the micro-camera with lamp, doctor passes through The image of the lamp observation gastrointestinal tract that pill or capsule 80 are passing through at this time.Capsule or pill 80 can have the power of their own Source, such as power is provided from outside by battery, or by antenna, so that laser diode 84 or other energy generate source wound Required wavelength and impulsive energy source are built to treat tissue to be treated and region.

As in the retinal treatment in previous application, chopping is radiated to utilize micropulse temperature peak and phase Safety, and regulating power are closed, so that treatment is completely harmless to tissue.This may include adjust peak power, the burst length, with And repetition rate, to be given at the peak value temperature rise of 10 DEG C of magnitude, while keeping FDA regulation limitation of the long-term temperature rise less than 1 DEG C. If can be provided by miniature rechargeable battery or by modes such as wireless induction excitations to device using the conveying of pill form 80 Power.It heat/stress organize that the activation of HSP will be stimulated or generation and promote albumen reparation and its additional benefits.

In from the example above, technology of the invention is limited at nearly body surface or is conveyed by optics or other optics The treatment for the situation at interior surface that device provides easy access to.Apply SDM or PEMR to activate HSP activity to be limited to the nearly table of body The reason of face or optics accessible areas is that the absorption length of the IR in body or visible radiation is very short.But, tissue or body The situation of internal deeper inside can benefit from the present invention.Therefore, the present invention considers using ultrasound and/or radio frequency (RF) and even more The electromagnetism (EM) of short wavelength radiates such as microwave, they have longer absorption length in bodily tissue.Opposite RF electromagnetism spoke It penetrates, usually preferentially using impulse ultrasound to activate remedial HSP activity in the abnormal structure that surface SDM etc. can not be approached.? Impulse ultrasound source can be used for the exception at surface or near surface.

Referring now to Figure 36, using ultrasound, microwave or radio frequency, by using focusing on one or more of target site respectively A beam can specially be directed at the specific region of body depths.Then, PULSE HEATING will be mainly only in the target area that light beam focuses and is overlapped In.

As shown in Figure 36, ultrasonic transducer 90 etc. generate multiple supersonic beams 92, they pass through sound-impedance-matching glue It is coupled to skin, and penetrates skin 94 and is placed through the non-injury tissue before the focus of beam 92 and reach target organ 96, such as Shown liver, and target tissue 98 to be treated is specifically reached, supersonic beam 92 focuses on this.As described above, then, PULSE HEATING The target focal zone 98 that will be only overlapped in focused beam acts 92.Tissue in 98 above and below of focal zone will not obviously be heated or shadow It rings.

The present invention not only considers to use such as focusing ultrasound such as by using treatment surface or near surface tissue laser RF or microwave light beam etc. treat deep tissue, and consider treatment hematologic disease and other dyscrasias, such as septicemia. As it appears from the above, focused ultrasound therapy, which can be not only used for surface, can also be used for deep bodily tissue, can also be applied to control in the case Treat blood.But, it is also considered that SDM and the similar PEMR treatment choosing on the surface or near surface treatment of epithelial cell etc. will be normally limited to Select for treat can region by relatively thin organized layer's (such as ear-lobe) close to blood or fluid blood or fluid disease.

Referring now to Figure 37 and Figure 38, the treatment of hematologic disease simply requires to transmit SDM or other electricity to ear-lobe 100 Magnetic radiation or ultrasonic pulse, wherein the SDM or other radiant energy sources can pass through ear-lobe tissue and pass into the blood of ear-lobe In.It is to be appreciated that the method can also betide in other regions of the body of the higher and/or close tissue surface of blood flow, Such as finger tip, mouth or inside of throat etc..

Referring again to Figure 37 and Figure 38, the neighbouring clamping device 102 for being configured to transmission SDM radiation etc. of ear-lobe 100 is shown. This can will be transmitted to ear-lobe 100 in required pulse and the required frequency of spike train for example with one or more laser diodes 104 Rate.Such as power can provide by lamp driver 106.Alternatively, lamp driver 106 can for by suitable optics and electronics to ear The practical laser sources of vertical 100 transmission.Clamping device 102 will only be used in the ear-lobe of clamping patient and make to radiate the ear-lobe for being limited to patient 100.This can be executed by mirror, reflector, diffuser etc..This can be controlled by control computer 108, which will pass through key The operation such as disk 110.If desired, if such as the process will be executed by the operator with a certain distance from patient, system may also include Display and loudspeaker 112.

As described above, although Figure 37 and Figure 38 are shown for illustrative purposes carries out body by the outer ear-lobe 100 provided easy access to The treatment of liquid i.e. blood, it will be appreciated that impulsive energy source of the invention can be applied to other perimeters of body, body The interior zone of body, and use various energy sources, including laser, radio frequency, microwave and ultrasound.Moreover, the present invention is not only to limit In the treatment of blood and hematologic disease, but can also be using other body fluid such as lymph etc..The type of treated body fluid can determine The region that fixed treatment occurs, such as when treating lymph, apply energy source in armpit, tonsillotome etc..

Although not specifically mentioned above, it will be appreciated that according to for therapeutic purposes or for preventative or protectiveness Disease to be treated and target tissue are treated, different disease or potential disease can be treated in different areas of body.For example, IPF can be applied locally via bronchoscope and be treated by PEMR infrared laser.Since heart is close to bronchial tree and lung, Heart disease can also pass through therapeutic bronchoscopy.Alternatively, as noted previously, as infrared absorption length is small, can be used PEMR radio frequency, Ultrasound or micro-wave therapeutic heart, lung etc..Additional advantage will not need that bronchoscope is inserted into the lung of patient and is caused not It is comfortable.

Again, selected treatment type and operating process and parameter can be according to the position changes of chronic progressive disease.For example, Alzheimer disease can be treated by applying RF to brain.The people of risk with cancer or with cancer can be according to the present invention Apply energy source to the organ of problematic body or region, no matter it be tissue or blood (not usually cancer itself, because The survival and growth of cancer can be enhanced for the activation of the HSP in cancer cell；But the component of immune system is treated, to enhance them The validity of anticancer).Even mental status such as depression may also be treated according to the present invention.

Present invention further contemplates that time-histories and possible power and other energy and operating parameter may need according to The tissue for the treatment of, the region of organ or body and change.For example, for idiopathic pulmonary fibrosis and other tuberculosis, due to right Stream can cool down lung tissue, it is thus possible to need to change such parameter.It allows individual to exhale and holds the breath several seconds and can also change Become these energy parameters, because inflation lung has the conductivity of 0.2S/m, and deflation lung has i.e. twice conductance of 0.41S/m Rate, and absorption length and the square root of conductivity are inversely proportional.Importance is to heat tissue or body fluid quickly to about 11 DEG C, simultaneously Keep lower temperature during a few minutes such as 6 minutes, such as less than 6 DEG C or even 1 DEG C.This will provide therapeutic benefits, example HSP is such as activated, while not damaging body fluid, cell and tissue.

Referring now to Figure 39, the risk of present invention consideration some diseases or disease may need to treat multiple areas of body Domain.For example, diabetes can be by applying microwave, RF etc. and be treated to many regions of body and possible entire body.Separately Outside, personal to suffer from a variety of chronic progressive diseases or may have the risk for suffering from a variety of chronic progressive diseases, it can The different zones of body can be needed to treat.Moreover, because the process for the treatment of according to the present invention seems only beneficial therapeutic And protectiveness therefore can be controlled using entire body as healthy cell as a result, without permanent damage or destroy cell or tissue Treat and tissue will not by the negative effect of the application of the impulsive energy source applied according to the present invention, and it is those of impaired will Benefit.

Correspondingly, please continue to refer to Figure 39, the present invention considers device 114, can be for example by individual in recumbency above Platform 118 keeps and/or supports entire body 116.It should be understood, however, that personal can be at different positions, such as stand, And it is not necessarily required to lie down.Device 114 will include pulse energy transmitter 120, can emit the pulse energy with above-mentioned parameter Amount source, to treat personal various types of tissues, organ, body fluid etc..This can for example with microwave, radio frequency (RF) and/or ultrasound, Or the light source of the body fluid even with outside or neighbouring such surface to treat personal body.Can corresponding treatment fluid, Problematic organ or other tissues.In fact, as described above, to treat entire body, it can be for example progressively or to predefine Mode transmitter 120 is for example moved to along track 122 different zones of body, to pass through heating region to scheduled temperature Degree treats required target tissue or target body liquid zone and/or entire body quickly, while keeping during longer period Scheduled lower temperature.Entire body treatment can be the summation of local treatment.This will be that for example treatment influences entire body or body The mode of the diabetes of the multiple regions of body and other similar diseases.For example, this can also be for example to use on the basis of a period of time In protectiveness and the system and method for the entire body of prophylactic treatment individual.

The treatment arranged using electromagnetism or ultrasonic pulse proposed with include single short or lasting (long) pulse There are two major advantages compared to tool for prior treatment.Firstly, short (preferably submicrosecond) single pulse active cell in the column Reset mechanism such as HSP activation has biggish anti-compared with those of operation on long period scale (minute or hour) Answer rate constant.Secondly, the repetition pulse in treatment provides big thermal peak (10000 magnitudes), allow the reparation of cell System overcomes the activation energy barrier for separating functional disturbance cell state and required function state quickly.Lower application can be used Mean power and it is total apply energy to obtain required therapeutic purpose, under this meaning, final result is " reduced treatment threshold Value ".

Although several embodiments are described in detail for the purpose of illustration here, the present invention can be made it is various change without departing from Scope and spirit of the present invention.Therefore, except as by the appended claims, the present invention is unrestricted.

Claims

1. a kind of biological tissue or stream for the risk with chronic progressive disease or with the chronic progressive disease of trouble Body provides the method for protectiveness treatment, comprising steps of

There is provided has the impulsive energy source including wavelength or frequency, the duty when energy parameter of spike train duration, the energy Amount parameter is selected to target tissue or target rehydration temperature being increased to 11 degrees Celsius, so that therapeutic or prophylactic effects are obtained, Wherein, the average temperature rising of the target tissue or target fluid is held in or lower than predeterminated level during several minutes, thus will not be forever The target tissue or target fluid are damaged long；And

Apply target tissue from the arteries and veins to the risk with chronic progressive disease or with the chronic progressive disease of trouble or target fluid Energy source is rushed, with the therapeutic or prophylactic treatment target tissue or target fluid.

2. the method for claim 1, wherein the step of application includes that the heat in the target tissue or target fluid is stimulated to stop The step of gram protein activation.

3. the method as described in claim 1, comprising steps of selecting the energy parameter of the impulsive energy source at least to the target Tissue or target fluid increase the target tissue or target fluid temperature (F.T.) in 6 degrees Celsius to 11 degrees Celsius during applying the impulsive energy source Between.

4. the method for claim 1, wherein the average temperature rising of the target tissue or target fluid is protected during several minutes It is held in 6 degrees Celsius or lower.

5. method as claimed in claim 4, wherein the average temperature rising of the target tissue or target fluid is protected during several minutes It is held in about 1 degree Celsius or lower.

6. method as claimed in claim 5, wherein mean temperature of the target tissue or target fluid during 6 minutes durations It is held in 1 degree Celsius or lower.

7. the method for claim 1, wherein the energy parameter of the impulsive energy source is chosen so that per cubic centimeter The target tissue or target fluid absorb 20 to 40 joules of energy.

8. the method for claim 1, wherein the step of application impulsive energy source includes being inserted into dress into body cavity It sets, to apply the impulsive energy source to the target tissue or target fluid.

9. the method for claim 1, wherein the step of application impulsive energy source includes drawing the impulsive energy source It is directed at the outside of body, adjacent to the target tissue or the target body liquid on the surface with the region close to the outside of the body supplies It answers.

10. the method as described in claim 1, including determine the target tissue or target fluid with chronic progressive disease or have The step of suffering from the risk of chronic progressive disease.

11. the method for claim 1, wherein apply the impulsive energy source to multiple target tissue regions, and wherein, Adjacent target tissue region is separated at least one preset distance, to avoid hot tissue damage.

12. the method for claim 1, wherein the impulsive energy source includes laser, microwave, radio frequency or ultrasound.

13. method as claimed in claim 12, wherein the impulsive energy source includes the radio frequency between 3 to 6 megahertzs, Duty ratio between 2.5% to 5%, and the spike train duration between 0.2 to 0.4 second.

14. method as claimed in claim 13, wherein the radio frequency pass through between 2 and 6 millimeters coil radius and Device between 13 and 57 ampere-turns generates.

15. method as claimed in claim 12, wherein the impulsive energy source include 10 to the microwave frequency between 20GHz, Spike train duration between 0.2 and 0.6 second, and the duty ratio between 2% to 5%.

16. method as claimed in claim 15, wherein the microwave has the mean power between 8 and 52 watts.

17. method as claimed in claim 12, wherein the impulsive energy source include have 530 nanometers to 1300 nanometers it Between wavelength, the duty ratio less than 10% and the pulsed light beam of the spike train duration between 0.1 and 0.6 second.

18. method as claimed in claim 17, wherein the pulsed light beam has the wave between 880 nanometers and 1000 nanometers The long and power between 0.5 and 74 watt.

19. method as claimed in claim 12, wherein the impulsive energy source includes with the frequency between about 1MHz and 5MHz The impulse ultrasound of rate, the column duration between 0.1 and 0.5 second and the duty ratio between 2% to 10%.

20. method as claimed in claim 19, wherein the ultrasound has the power between 0.46 and 28.6 watt.

21. a kind of biological tissue or stream for the risk with chronic progressive disease or with the chronic progressive disease of trouble Body provides the method for protectiveness treatment, comprising steps of

Determine target tissue or target body liquid with chronic progressive disease or with the risk for suffering from chronic progressive disease；

There is provided have including wavelength or frequency, duty when the laser of the energy parameter of spike train duration, microwave, radio frequency or The impulsive energy source of ultrasound, the energy parameter are selected to target tissue or target body liquid at least during applying the impulsive energy source Temperature increases between 6 and 11 degrees Celsius, to obtain therapeutic or prophylactic effects, wherein the target group during several minutes It knits or the average temperature rising of target fluid is held in or is lower than 6 degrees Celsius, thus will not the permanent damage target tissue or target fluid；With And

To the target tissue or the target stream being determined with chronic progressive disease or with the risk for suffering from chronic progressive disease Body applies the impulsive energy source, with the therapeutic or prophylactic treatment target tissue or target fluid.

22. method as claimed in claim 21, wherein the step of application includes the heat stimulated in the target tissue or target fluid The step of shock protein activates.

23. method as claimed in claim 21, wherein the average temperature of this of the target tissue or target fluid during 6 minutes durations Degree is held in 1 degree Celsius or lower.

24. method as claimed in claim 21, wherein the parameter of the impulsive energy source is chosen so that per cubic centimeter be somebody's turn to do Target tissue or target fluid absorb 20 to 40 joules of energy.

25. method as claimed in claim 21, wherein the step of application impulsive energy source includes being inserted into dress into body cavity It sets, to apply the impulsive energy source to the target tissue or target fluid.

26. method as claimed in claim 21, wherein include by the impulsive energy source the step of application impulsive energy source Guidance is to the outside of body, and adjacent to the target tissue or the target body liquid on the surface with the region close to the outside of the body supplies It answers.

27. method as claimed in claim 21, wherein apply the impulsive energy source to multiple target tissue regions, and wherein, Adjacent target tissue region is separated at least one preset distance, to avoid hot tissue damage.

28. method as claimed in claim 21, wherein the impulsive energy source includes the radio frequency between 3 to 6 megahertzs, Duty ratio between 2.5% to 5%, and the spike train duration between 0.2 to 0.4 second.

29. method as claimed in claim 28, wherein the radio frequency pass through between 2 and 6 millimeters coil radius and Device between 13 and 57 ampere-turns generates.

30. method as claimed in claim 21, wherein the impulsive energy source include 10 to the microwave frequency between 20GHz, Spike train duration between 0.2 and 0.6 second, and the duty ratio between 2% to 5%.

31. method as claimed in claim 30, wherein the microwave has the mean power between 8 and 52 watts.

32. method as claimed in claim 21, wherein the impulsive energy source include have 530 nanometers to 1300 nanometers it Between wavelength, the duty ratio less than 10% and the pulsed light beam of the spike train duration between 0.1 and 0.6 second.

33. method as claimed in claim 32, wherein the pulsed light beam has the wave between 880 nanometers and 1000 nanometers The long and power between 0.5 and 74 watt.

34. method as claimed in claim 21, wherein the impulsive energy source includes with the frequency between about 1MHz and 5MHz The impulse ultrasound of rate, the column duration between 0.1 and 0.5 second and the duty ratio between 2% to 10%.

35. method as claimed in claim 34, wherein the ultrasound has the power between 0.46 and 28.6 watt.