AU2020213374B2 - Method for heat treating biological tissues using pulsed energy sources - Google Patents

Abstract

A method for heat treating biological tissues includes providing a pulsed energy source having energy parameters selected so as to raise a target temperature to a level to achieve a therapeutic effect, while the average temperature rise of the tissue over a prolonged period of time is maintained at or below a predetermined level so as not to permanently damage the target tissue. Application of the pulsed energy source to the target tissue induces a heat shock response and stimulates heat shock protein activation in the target tissue so as to therapeutically treat the target tissue. Page 59

Description

SYSTEM ADAPTED TO PERFORM METHODS FOR HEAT TREATING BIOLOGICAL TISSUES USING PULSED ENERGY SOURCES DESCRIPTION BACKGROUND OF THE INVENTION

[Para 1] The present invention is generally directed to a system adapted to

perform methods for heat treating biological tissues. More particularly, the

present invention is directed to a system adapted to perform a method for

applying a pulsed energy source to biological tissue to stimulate activation of

heat shock proteins and facilitate protein repair without damaging the tissue.

[Para 2] The inventors have discovered that there is a therapeutic effect to

biological tissue, and particularly damaged or diseased biological tissue, by

controllably elevating the tissue temperature up to a predetermined

temperature range while maintaining the average temperature rise of the tissue

over several minutes at or below a predetermined level so as not to

permanently damage the target tissue. It is believed that raising the tissue

temperature in such a controlled manner selectively stimulates heat shock

protein activation and/or production and facilitation of protein repair, which

serves as a mechanism for therapeutically treating the tissue.

[Para 3] Heat shock proteins (HSPs) are a family of proteins that are produced

by cells in response to exposure to stressful conditions. Production of high

Page 1 16522060_1 (GHMattes) P108158.AU.1 levels of heat shock proteins can be triggered by exposure to different kinds of environmental stress conditions, such as infection, inflammation, exercise, exposure of the cell to toxins, starvation, hypoxia, or water deprivation.

[Para 4] It is known that heat shock proteins play a role in responding to a

large number of abnormal conditions in body tissues, including viral infection,

inflammation, malignant transformations, exposure to oxidizing agents,

cytotoxins, and anoxia. Several heat shock proteins function as intra-cellular

chaperones for other proteins and members of the HSP family are expressed or

activated at low to moderate levels because of their essential role in protein

maintenance and simply monitoring the cell's proteins even under non

stressful conditions. These activities are part of a cell's own repair system,

called the cellular stress response or the heat-shock response.

[Para 5] Heat shock proteins are typically named according to their molecular

weight. For example, Hsp60, Hsp70 and Hsp80 refer to the families of heat

shock proteins on the order of 60, 70 and 80 kilodaltons in size, respectively.

They act in a number of different ways. For example, Hsp70 has peptide

binding and ATPase domains that stabilize protein structures in unfolded and

assembly-competent states. Mitochondrial Hsp60s form ring-shaped

structures facilitating the assembly of proteins into native states. Hsp90 plays a

suppressor regulatory role by associating with cellular tyrosine kinases,

transcription factors, and glucocorticoid receptors. Hsp27 suppresses protein

aggregation.

Page 2 16522060_1 (GHMatters) P108158.AU.1

[Para 6] Hsp70 heat shock proteins are a member of extracellular and

membrane bound heat-shock proteins which are involved in binding antigens

and presenting them to the immune system. Hsp70 has been found to inhibit

the activity of influenza A virus ribonucleoprotein and to block the replication

of the virus. Heat shock proteins derived from tumors elicit specific protective

immunity. Experimental and clinical observations have shown that heat shock

proteins are involved in the regulation of autoimmune arthritis, type I diabetes,

mellitus, arterial sclerosis, multiple sclerosis, and other autoimmune reactions.

[Para 7] Accordingly, it is believed that it is advantageous to be able to

selectively and controllably raise a target tissue temperature up to a

predetermined temperature range over a short period of time, while

maintaining the average temperature rise of the tissue at a predetermined

temperature over a longer period of time. It is believed that this induces the

heat shock response in order to increase the number or activity of heat shock

proteins in body tissue in response to infection or other abnormalities.

However, this must be done in a controlled manner in order not to damage or

destroy the tissue or the area of the body being treated. The present invention

fulfills these needs, and provides other related advantages.

SUMMARY OF THE INVENTION

[Para 8] One aspect of the present invention is directed to a method for heat

treating biological tissues by applying a pulsed energy source to the target

tissue to therapeutically treat the target tissue. The pulsed energy source has

Page 3 16522060_1 (GHMattes) P108158.AU.1 energy parameters including wavelength or frequency, duty cycle and pulse train duration. The energy parameters are selected so as to raise a target tissue temperature up to 11°C to achieve a therapeutic effect, wherein the average temperature rise of the tissue over several minutes is maintained at or below a predetermined level so as not to permanently damage the target tissue.

[Para9] Another aspect of the present invention is directed to system adapted

to perform a method for heat treating biological tissues by applying a pulsed

energy source to the target tissue to therapeutically treat the target tissue. The

pulsed energy source has energy parameters including wavelength or

frequency, duty cycle and pulse train duration. The energy parameters are

selected so as to raise a target tissue temperature up to 11°C to achieve a

therapeutic effect, wherein the average temperature rise of the tissue over

several minutes is maintained at or below a predetermined level so as not to

permanently damage the target tissue.

[Para 10] Another aspect of the present invention is directed to system adapted

to heat treat biological tissues, comprising: a pulsed energy source having

energy parameters including wavelength or frequency, power and a duty cycle

of 10% or less that raises a target tissue temperature between approximately

six and eleven degrees Celsius at least during application of the pulsed energy

source to the target tissue for a pulsed train duration of less than one second,

wherein the average temperature rise of the tissue over six minutes or less is

maintained at or below six degrees Celsius so as to not permanently damage

the target tissue.

Page 4 16522060_1 (GHMatters) P108158.AU.1

[Para 11] The energy source parameters may be selected so that the target

tissue temperature is raised between approximately 6°C to 11°C at least during

application of the pulsed energy source to the target tissue. The average

temperature rise of the target tissue over several minutes is maintained at 6°C

or less, such as at approximately 1°C or less over several minutes.

[Para 12] The pulsed energy source energy parameters are selected so that

approximately 20 to 40 joules of energy is absorbed by each cubic centimeter

of the target tissue. Applying the pulsed energy source to the target tissue

induces a heat shock response and stimulates heat shock protein activation in

the target tissue without damaging the target tissue.

[Para 13] A device may be inserted into a cavity of the body in order to apply

the pulsed energy to the tissue. The pulsed energy may be applied to an

exterior area of a body which is adjacent to the target tissue, or has a blood

supply close to a surface of the exterior area of the body.

[Para 14] The pulsed energy source may comprise a radiofrequency. The

radiofrequency may be between approximately 3 to 6 megahertz (MHz). It may

have a duty cycle of between approximately 2.5% to 5%. It may have a pulsed

train duration of between approximately 0.2 to 0.4 seconds. The

radiofrequency may be generated with a device having a coil radii of between

approximately 2 and 6 mm and approximately 13 and 57 amp turns.

[Para 15] The pulsed energy source may comprise a microwave frequency of

between 10 to 20 gigahertz (GHz). The microwave may have a pulse train

duration of approximately between 0.2 and 0.6 seconds. The microwave may

Page 5 16522060_1 (GHMatters) P108158.AU.1 have a duty cycle of between approximately 2% and 5%. The microwave may have an average power of between approximately 8 and 52 watts.

[Para 16] The pulsed energy source may comprise a pulsed light beam, such

as a laser light. The light beam may have a wavelength of between

approximately 530 nm to 1300 nm, and more preferably between 800 nm and

1000 nm. The pulsed light beam may have a power of between approximately

0.5 and 74 watts. The pulsed light beam has a duty cycle of less than 10%, and

preferably between 2.5% and 5%. The pulsed light beam may have a pulse train

duration of approximately 0.1 and 0.6 seconds.

[Para 17] The pulsed energy source may comprise a pulsed ultrasound. The

ultrasound has a frequency of between approximately 1 and 5 MHz. The

ultrasound has a train duration of approximately 0.1 and 05 seconds. The

ultrasound may have a duty cycle of between approximately 2% and 10%. The

ultrasound has a power of between approximately 0.46 and 28.6 watts.

[Para 18] Other features and advantages of the present invention will become

apparent from the following more detailed description, taken in conjunction

with the accompanying drawings, which illustrate, by way of example, the

principles of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[Para 19] The accompanying drawings illustrate the invention. In such

drawings:

Page 6 16522060_1 (GHMattes) P108158.AU.1

[Para 20] FIGURES 1A and 1B are graphs illustrating the average power of a

laser source compared to a source radius and pulse train duration of the laser;

[Para 21] FIGURES 2A and 2B are graphs illustrating the time for the

temperature to decay depending upon the laser source radius and wavelength;

[Para 22] FIGURES 3-6 are graphs illustrating the peak ampere turns for

various radiofrequencies, duty cycles, and coil radii;

[Para 23] FIGURE 7 is a graph depicting the time for temperature rise to

decay compared to radiofrequency coil radius;

[Para 24] FIGURES 8 and 9 are graphs depicting the average microwave

power compared to microwave frequency and pulse train durations;

[Para 25] FIGURE 10 is a graph depicting the time for the temperature to

decay for various microwave frequencies;

[Para 26] FIGURE 11is a graph depicting the average ultrasound source

power compared to frequency and pulse train duration;

[Para 27] FIGURES 12 and 13 are graphs depicting the time for temperature

decay for various ultrasound frequencies;

[Para 28] FIGURE 14 is a graph depicting the volume of focal heated region

compared to ultrasound frequency;

[Para 29] FIGURE 15 is a graph comparing equations for temperature over

pulse durations for an ultrasound energy source;

[Para 30] FIGURES 16 and 17 are graphs illustrating the magnitude of the

logarithm of damage and HSP activation Arrhenius integrals as a function of

temperature and pulse duration;

Page 7 16522060_1 (GHMatters) P108158.AU.1

[Para 31] FIGURE 18 is a diagrammatic view of a light generating unit that

produces timed series of pulses, having a light pipe extending therefrom, in

accordance with the present invention;

[Para 32] FIGURE 19 is a cross-sectional view of a photostimulation delivery

device delivering electromagnetic energy to target tissue, in accordance with

the present invention;

[Para 33] FIGURE 20 is a diagrammatic view illustrating a system used to

generate a laser light beam, in accordance with the present invention;

[Para 34] FIGURE 21 is a diagrammatic view of optics used to generate a laser

light geometric pattern, in accordance with the present invention;

[Para 35] FIGURE 22 is a diagrammatic view illustrating an alternate

embodiment of the system used to generate laser light beams for treating

tissue, in accordance with the present invention;

[Para 36] FIGURE 23 is a diagrammatic view illustrating yet another

embodiment of a system used to generate laser light beams to treat tissue in

accordance with the present invention;

[Para 37] FIGURE 24 is a cross-sectional and diagrammatic view of an end of

an endoscope inserted into the nasal cavity and treating tissue therein, in

accordance with the present invention;

[Para 38] FIGURE 25 is a diagrammatic and partially cross-sectioned view of

a bronchoscope extending through the trachea and into the bronchus ofa lung

and providing treatment thereto, in accordance with the present invention;

Page 8 16522060_1 (GHMatters) P108158.AU.1

[Para 39] FIGURE 26 is a diagrammatic view of a colonoscope providing

photostimulation to an intestinal or colon area of the body, in accordance with

the present invention;

[Para 40] FIGURE 27 is a diagrammatic view of an endoscope inserted into a

stomach and providing treatment thereto, in accordance with the present

invention;

[Para 41] FIGURE 28 is a partially sectioned perspective view of a capsule

endoscope, used in accordance with the present invention;

[Para 42] FIGURE 29 is a diagrammatic view of a pulsed high intensity

focused ultrasound for treating tissue internal the body, in accordance with the

present invention;

[Para 43] FIGURE 30 is a diagrammatic view for delivering therapy to the

bloodstream of a patient, through an earlobe, in accordance with the present

invention;

[Para 44] FIGURE 31 is a cross-sectional view of a stimulating therapy device

of the present invention used in delivering photostimulation to the blood, via an

earlobe, in accordance with the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[Para 45] As shown in the accompanying drawings, and as more fully

described herein, the present invention is directed to a system and method for

delivering a pulsed energy source, such as laser, ultrasound, ultraviolet

radiofrequency, microwave radiofrequency and the like, having energy

Page 9 16522060_1 (GHMattes) P108158.AU.1 parameters selected to cause a thermal time-course in tissue to raise the tissue temperature over a short period of time to a sufficient level to achieve a therapeutic effect while maintaining an average tissue temperature over a prolonged period of time below a predetermined level so as to avoid permanent tissue damage. It is believed that the creation of the thermal time-course stimulates heat shock protein activation or production and facilitates protein repair without causing any damage.

[Para 46] The inventors of the present invention have discovered that

electromagnetic radiation, in the form of various wavelengths of laser light, can

be applied to retinal tissue in a manner that does not destroy or damage the

retinal tissue while achieving beneficial effects on eye diseases. It is believed

that this may be due, at least in part, to the stimulation and activation of heat

shock proteins and the facilitation of protein repair in the retinal tissue. This is

disclosed in United States patent application serial numbers 14/607,959 filed

January 28, 2015, 13/798,523 filed March 13, 2013, and 13/481,124 filed May

, 2012, the contents of which are hereby incorporated by reference as if

made in full.

[Para 47] The inventors have found that a laser light beam can be generated

that is therapeutic, yet sublethal to retinal tissue cells and thus avoids

damaging photocoagulation in the retinal tissue which provides preventative

and protective treatment of the retinal tissue of the eye. Various parameters of

the light beam must be taken into account and selected so that the combination

of the selected parameters achieve the therapeutic effect while not permanently

Page 10 16522060_1 (GHMatters) P108158.AU.1 damaging the tissue. These parameters include laser wavelength, radius of the laser source, average laser power, total pulse duration, and duty cycle of the pulse train.

[Para 48] The selection of these parameters may be determined by requiring

that the Arrhenius integral for HSP activation be greater than 1 or unity.

Arrhenius integrals are used for analyzing the impacts of actions on biological

tissue. See, for instance, The CRC Handbook of Thermal Engineering, ed. Frank

Kreith, Springer Science and Business Media (2000). At the same time, the

selected parameters must not permanently damage the tissue. Thus, the

Arrhenius integral for damage may also be used, wherein the solved Arrhenius

integral is less than 1 or unity. Alternatively, the FDA/FCC constraints on

energy deposition per unit gram of tissue and temperature rise as measured

over periods of minutes be satisfied so as to avoid permanent tissue damage.

The FDA/FCC requirements on energy deposition and temperature rise are

widely used and can be referenced, for example, at

www.fda.gov/medicaldevices/deviceregulationandguidance/guidancedocument

s/ucm073817.htm#attacha for electromagnetic sources, and Anastosio and P.

LaRivero, ed., Emerging Imaging Technologies. CRC Press (2012), for

ultrasound sources. Generally speaking, tissue temperature rises of between

6°C and 11°C can create therapeutic effect, such as by activating heat shock

proteins, whereas maintaining the average tissue temperature over a prolonged

period of time, such as over several minutes, such as six minutes, below a

Page 11 16522060_1 (GHMatters) P108158.AU.1 predetermined temperature, such as 6°C and even 1°C or less in certain circumstances, will not permanently damage the tissue.

[Para 49] The inventors have discovered that generating a subthreshold,

sublethal micropulse laser light beam which has a wavelength greater than 532

nm and a duty cycle of less than 10% at a predetermined intensity or power and

a predetermined pulse length or exposure time creates desirable retinal

photostimulation without any visible burn areas or tissue destruction. More

particularly, a laser light beam having a wavelength of between 550 nm-1300

nm, and in a particularly preferred embodiment between 810 nm and 1000 nm,

having a duty cycle of approximately 2.5%-5% and a predetermined intensity or

power (such as between 100-590 watts per square centimeter at the retina or

approximately 1 watt per laser spot for each treatment spot at the retina) and a

predetermined pulse length or exposure time (such as between 100 and 600

milliseconds or less) creates a sublethal, "true subthreshold" retinal

photostimulation in which all areas of the retinal pigment epithelium exposed

to the laser irradiation are preserved and available to contribute therapeutically.

In other words, the inventors have found that raising the retinal tissue at least

up to a therapeutic level but below a cellular or tissue lethal level recreates the

benefit of the halo effect of the prior art methods without destroying, burning

or otherwise damaging the retinal tissue. This is referred to herein as

subthreshold diode micropulse laser treatment (SDM).

[Para 50] As SDM does not produce laser-induced retinal damage

(photocoagulation), and has no known adverse treatment effect, and has been

Page 12 16522060_1 (GHMatters) P108158.AU.1 reported to be an effective treatment in a number of retinal disorders (including diabetic macular edema (DME) proliferative diabetic retinopathy (PDR), macular edema due to branch retinal vein occlusion (BRVO), central serous chorioretinopathy (CSR), reversal of drug tolerance, and prophylactic treatment of progressive degenerative retinopathies such as dry age-related macular degeneration, Stargardts' disease, cone dystrophies, and retinitis pigmentosa.

The safety of SDM is such that it may be used transfoveally in eyes with 20/20

visual acuity to reduce the risk of visual loss due to early fovea-involving DME.

[Para 51] A mechanism through which SDM might work is the generation or

activation of heat shock proteins (HSPs). Despite a near infinite variety of

possible cellular abnormalities, cells of all types share a common and highly

conserved mechanism of repair: heat shock proteins (HSPs). HSPs are elicited

almost immediately, in seconds to minutes, by almost any type of cell stress or

injury. In the absence of lethal cell injury, HSPs are extremely effective at

repairing and returning the viable cell toward a more normal functional state.

Although HSPs are transient, generally peaking in hours and persisting for a few

days, their effects may be long lasting. HSPs reduce inflammation, a common

factor in many disorders.

[Para 52] Laser treatment can induce HSP production or activation and alter

cytokine expression. The more sudden and severe the non-lethal cellular stress

(such as laser irradiation), the more rapid and robust HSP activation. Thus, a

burst of repetitive low temperature thermal spikes at a very steep rate of

change (- 7°C elevation with each 100ps micropulse, or 70,000°C/sec)

Page 13 16522060_1 (GHMatters) P108158.AU.1 produced by each SDM exposure is especially effective in stimulating activation of HSPs, particularly compared to non-lethal exposure to subthreshold treatment with continuous wave lasers, which can duplicate only the low average tissue temperature rise.

[Para 53] Laser wavelengths below 550 nm produce increasingly cytotoxic

photochemical effects. At 810 nm, SDM produces photothermal, rather than

photochemical, cellular stress. Thus, SDM is able to affect the tissue without

damaging it. The clinical benefits of SDM are thus primarily produced by sub

morbid photothermal cellular HSP activation. In dysfunctional cells, HSP

stimulation by SDM results in normalized cytokine expression, and

consequently improved structure and function. The therapeutic effects of this

"low-intensity" laser/tissue interaction are then amplified by "high-density"

laser application, recruiting all the dysfunctional cells in the targeted tissue

area by densely / confluently treating a large tissue area, including all areas of

pathology, thereby maximizing the treatment effect. These principles define the

treatment strategy of SDM described herein.

[Para 54] Because normally functioning cells are not in need of repair, HSP

stimulation in normal cells would tend to have no notable clinical effect. The

"patho-selectivity" of near infrared laser effects, such as SDM, affecting sick

cells but not affecting normal ones, on various cell types is consistent with

clinical observations of SDM. SDM has been reported to have a clinically broad

therapeutic range, unique among retinal laser modalities, consistent with

American National Standards Institute "Maximum Permissible Exposure"

Page 14 16522060_1 (GHMatters) P108158.AU.1 predictions. While SDM may cause direct photothermal effects such as entropic protein unfolding and disaggregation, SDM appears optimized for clinically safe and effective stimulation of HSP-mediated repair.

[Para 55] As noted above, while SDM stimulation of HSPs is non-specific with

regard to the disease process, the result of HSP mediated repair is by its nature

specific to the state of the dysfunction. HSPs tend to fix what is wrong,

whatever that might be. Thus, the observed effectiveness of SDM in retinal

conditions as widely disparate as BRVO, DME, PDR, CSR, age-related and

genetic retinopathies, and drug-tolerant NAMD. Conceptually, this facility can

be considered a sort of "Reset to Default" mode of SDM action. For the wide

range of disorders in which cellular function is critical, SDM normalizes cellular

function by triggering a "reset" (to the "factory default settings") via HSP

mediated cellular repair.

[Para 56] The inventors have found that SDM treatment of patients suffering

from age-related macular degeneration (AMD) can slow the progress or even

stop the progression of AMD. Most of the patients have seen significant

improvement in dynamic functional logMAR mesoptic visual acuity and

mesoptic contrast visual acuity after the SDM treatment. It is believed that SDM

works by targeting, preserving, and "normalizing" (moving toward normal)

function of the retinal pigment epithelium (RPE).

[Para 57] SDM has also been shown to stop or reverse the manifestations of

the diabetic retinopathy disease state without treatment-associated damage or

adverse effects, despite the persistence of systemic diabetes mellitus. On this

Page 15 16522060_1 (GHMatters) P108158.AU.1 basis it is hypothesized that SDM might work by inducing a return to more normal cell function and cytokine expression in diabetes-affected RPE cells, analogous to hitting the "reset" button of an electronic device to restore the factory default settings. Based on the above information and studies, SDM treatment may directly affect cytokine expression via heat shock protein (HSP) activation in the targeted tissue.

[Para 58] As heat shock proteins play a role in responding to a large number

of abnormal conditions in body tissue other than eye tissue, it is believed that

similar systems and methodologies can be advantageously used in treating

such abnormal conditions, infections, etc. As such, the present invention is

directed to the controlled application of ultrasound or electromagnetic radiation

to treat abnormal conditions including inflammations, autoimmune conditions,

and cancers that are accessible by means of fiber optics of endoscopes or

surface probes as well as focused electromagnetic/sound waves. For example,

cancers on the surface ofthe prostate that have the largest threat of

metastasizing can be accessed by means of fiber optics in a proctoscope.

Colon tumors can be accessed by an optical fiber system, like those used in

colonoscopy.

[Para 59] As indicated above, subthreshold diode micropulse laser (SDM)

photostimulation has been effective in stimulating direct repair of slightly

misfolded proteins in eye tissue. Besides HSP activation, another way this may

occur is because the spikes in temperature caused by the micropulses in the

form of a thermal time-course allows diffusion of water inside proteins, and

Page 16 16522060_1 (GHMatters) P108158.AU.1 this allows breakage of the peptide-peptide hydrogen bonds that prevent the protein from returning to its native state. The diffusion of water into proteins results in an increase in the number of restraining hydrogen bonds by a factor on the order of a thousand. Thus, it is believed that this process could be applied to other diseases advantageously as well.

[Para 60] As explained above, the energy source to be applied to the target

tissue will have energy and operating parameters which must be determined

and selected so as to achieve the therapeutic effect while not permanently

damaging the tissue. Using a light beam energy source, such as a laser light

beam, as an example, the laser wavelength, duty cycle and total pulse train

duration parameters must be taken into account. Other parameters which can

be considered include the radius of the laser source as well as the average laser

power. Adjusting or selecting one of these parameters can have an effect on at

least one other parameter.

[Para 61] FIGS. 1A and 1B illustrate graphs showing the average power in

watts as compared to the laser source radius (between 0.1 cm and 0.4 cm) and

pulse train duration (between 0.1 and 0.6 seconds). FIG. 1A shows a

wavelength of 880 nm, whereas FIG.1B has a wavelength of 1000 nm. It can be

seen in these figures that the required power decreases monotonically as the

radius of the source decreases, as the total train duration increases, and as the

wavelength decreases. The preferred parameters for the radius of the laser

source is 1 mm-4 mm. For a wavelength of 880 nm, the minimum value of

power is 0.55 watts, with a radius of the laser source being 1 mm, and the total

Page 17 16522060_1 (GHMatters) P108158.AU.1 pulse train duration being 600 milliseconds. The maximum value of power for the 880 nm wavelength is 52.6 watts when the laser source radius is 4 mm and the total pulse drain duration is 100 milliseconds. However, when selecting a laser having a wavelength of 1000 nm, the minimum power value is 0.77 watts with a laser source radius of 1 mm and a total pulse train duration of 600 milliseconds, and a maximum power value of 73.6 watts when the laser source radius is 4 mm and the total pulse duration is 100 milliseconds. The corresponding peak powers, during an individual pulse, are obtained from the average powers by dividing by the duty cycle.

[Para 62] The volume of the tissue region to be heated is determined by the

wavelength, the absorption length in the relevant tissue, and by the beam

width. The total pulse duration and the average laser power determine the total

energy delivered to heat up the tissue, and the duty cycle of the pulse train

gives the associated spike, or peak, power associated with the average laser

power. Preferably, the pulsed energy source energy parameters are selected so

that approximately 20 to 40 joules of energy is absorbed by each cubic

centimeter of the target tissue.

[Para 63] The absorption length is very small in the thin melanin layer in the

retinal pigmented epithelium. In other parts of the body, the absorption length

is not generally that small. In wavelengths ranging from 400 nm to 2000 nm,

the penetration depth and skin is in the range of 0.5 mm to 3.5 mm. The

penetration depth into human mucous tissues in the range of 0.5 mm to 6.8

mm. Accordingly, the heated volume will be limited to the exterior or interior

Page 18 16522060_1 (GHMatters) P108158.AU.1 surface where the radiation source is placed, with a depth equal to the penetration depth, and a transverse dimension equal to the transverse dimension of the radiation source. Since the light beam energy source is used to treat diseased tissues near external surfaces or near internal accessible surfaces, a source radii of between 1 mm to 4 mm and operating a wavelength of 880 nm yields a penetration depth of approximately 2.5 mm and a wavelength of 1000 nm yields a penetration depth of approximately 3.5 mm.

[Para 64] It has been determined that the target tissue can be heated to up to

approximately 11C for a short period of time, such as less than one second, to

create the therapeutic effect of the invention while maintaining the target tissue

average temperature to a lower temperature range, such as less than 6°C or

even 1C or less over a prolonged period of time, such as several minutes. The

selection of the duty cycle and the total pulse train duration provide time

intervals in which the heat can dissipate. A duty cycle of less than 10%, and

preferably between 2.5% and 5%, with a total pulse duration of between 100

milliseconds and 600 milliseconds has been found to be effective. FIGS. 2A and

2B illustrate the time to decay from 10°C to 1C for a laser source having a

radius of between 0.1 cm and 0.4 cm with the wavelength being 880 nm in FIG.

2A and 1000 nm in FIG. 2B. It can be seen that the time to decay is less when

using a wavelength of 880 nm, but either wavelength falls within the acceptable

requirements and operating parameters to achieve the benefits of the present

invention while not causing permanent tissue damage.

Page 19 16522060_1 (GHMatters) P108158.AU.1

[Para 65] It has been found that the average temperature rise of the desired

target region increasing at least 6°C and up to11°C, and preferably

approximately 10°C, during the total irradiation period results in HSP activation.

The control of the target tissue temperature is determined by choosing source

and target parameters such that the Arrhenius integral for HSP activation is

larger than 1, while at the same time assuring compliance with the conservative

FDA/FCC requirements for avoiding damage or a damage Arrhenius integral

being less than 1.

[Para 66] In order to meet the conservative FDA/FCC constraints to avoid

permanent tissue damage, for light beams, and other electromagnetic radiation

sources, the average temperature rise of the target tissue over any six-minute

period is 1°C or less. FIGS. 2A and 2B above illustrate the typical decay times

required for the temperature in the heated target region to decrease by thermal

diffusion from a temperature rise of approximately 10°C to 1°C as can be seen

in FIG. 2A when the wavelength is 880 nm and the source diameter is 1

millimeter, the temperature decay time is 16 seconds. The temperature decay

time is 107 seconds when the source diameter is 4 mm. As shown in FIG. 2B,

when the wavelength is 1000 nm, the temperature decay time is 18 seconds

when the source diameter is 1 mm and 136 seconds when the source diameter

is 4 mm. This is well within the time of the average temperature rise being

maintained over the course of several minutes, such as 6 minutes or less. While

the target tissue's temperature is raised, such as to approximately10°C, very

quickly, such as in a fraction of a second during the application of the energy

Page 20 16522060_1 (GHMatters) P108158.AU.1 source to the tissue, the relatively low duty cycle provides relatively long periods of time between the pulses of energy applied to the tissue and the relatively short pulse train duration ensure sufficient temperature diffusion and decay within a relatively short period of time comprising several minutes, such as 6 minutes or less, that there is no permanent tissue damage.

[Para 67] The parameters differ for the individual energy sources, including

microwave, infrared lasers, radiofrequency and ultrasound, because the

absorption properties of tissues differ for these different types of energy

sources. The tissue water content can vary from one tissue type to another,

however, there is an observed uniformity of the properties of tissues at normal

or near normal conditions which has allowed publication of tissue parameters

that are widely used by clinicians in designing treatments. Below are tables

illustrating the properties of electromagnetic waves in biological media, with

Table 1 relating to muscle, skin and tissues with high water content, and Table

2 relating to fat, bone and tissues with low water content.

[Para 68] Table 1. Properties of Electromagnetic Waves in Biological Media: Muscle, Skin, and Tissues with High Water Content Reflection Coefficient Wavelength Dielectric Conductivity Wavelength Depth of Air-Muscle Interface Muscle-Fat Interface Frequency in Air Constant c-H XH Penetration (MHz) (cm) EH (mho/m) (cm) (cm) r 0 r 0 1 30000 2000 0.400 436 91.3 0.982 ±179 10 3000 160 0.625 118 21.6 0.956 ±178 27.12 1106 113 0.612 68.1 14.3 0.925 +177 0.651 -11.13 40.68 738 97.3 0.693 51.3 11.2 0.913 +176 0.652 -10.21 100 300 71.7 0.889 27 6.66 0.881 +175 0.650 -7.96 200 150 56.5 1.28 16.6 4.79 0.844 +175 0.612 -8.06 300 100 54 1.37 11.9 3.89 0.825 +175 0.592 -8.14 433 69.3 53 1.43 8.76 3.57 0.803 +175 0.562 -7.06 750 40 52 1.54 5.34 3.18 0.779 +176 0.532 -5.69 915 32.8 51 1.60 4.46 3.04 0.772 +177 0.519 -4.32

Page 21 16522060_1 (GHMatters) P108158.AU.1

1500 20 49 1.77 2.81 2.42 0.761 +177 0.506 -3.66 2450 12.2 47 2.21 1.76 1.70 0.754 +177 0.500 -3.88 3000 10 46 2.26 1.45 1.61 0.751 +178 0.495 -3.20 5000 6 44 3.92 0,89 0.788 0.749 +177 0.502 -4.95 5800 5.17 43.3 4.73 0.775 0.720 0.746 +177 0.502 -4.29 8000 3,75 40 7.65 0.578 0.413 0.744 +176 0.513 -6.65 10000 3 39.9 10.3 0.464 0.343 0.743 +176 0.518 -5.95

[Para 69] Table 2. Properties of Electromagnetic Waves in Biological Media: Fat, Bone, and Tissues with Low Water Content Reflection Coefficient Wavelength Dielectric Conductivity Wavelength Depth of Air-Fat Interface Fat-Muscle Interface Frequency in Air Constant c-L, XL Penetration (MHz) (cm) EL (mmho/m) (cm (cm) r 0 r 0 1 30000 10 3000 27.12 1106 20 10.9-43.2 241 159 0.660 +174 0.651 +169 40.68 738 14.6 12.6-52.8 187 118 0.617 +173 0.652 +170 100 300 7.45 19.1-75.9 106 60.4 0.511 +168 0.650 +172 200 150 5.95 25.8-94.2 59.7 39.2 0.458 +168 0.612 +172

300 100 5.7 31.6-107 41 32.1 0.438 +169 0.592 +172 433 69.3 5.6 37.9-118 28.8 26.2 0.427 +170 0.562 +173 750 40 5.6 49.8-138 16.8 23 0.415 +173 0.532 +174 915 32.8 5.6 55.6-147 13.7 17.7 0.417 +173 0.519 +1 76 1500 20 5.6 70.8-171 8.41 13.9 0.412 +174 0.506 +176 2450 12.2 5.5 96.4-213 5.21 11.2 0.406 +176 0.500 +176 3000 10 5.5 110-234 4.25 9.74 0.406 +176 0.495 +177 5000 6 5.5 162-309 2.63 6.67 0.393 +176 0.502 +175 5900 5.17 5.05 186-338 2.29 5.24 0.388 +176 0.502 +176 8000 3.75 4.7 255-431 1.73 4.61 0.371 +176 0.513 +173 10000 3 4.5 324-549 1.41 3.39 0.363 +175 0.518 +174,

[Para 70] The absorption lengths of radiofrequency in body tissue are long

compared to body dimensions. Consequently, the heated region is determined

by the dimensions of the coil that is the source of the radiofrequency energy

rather than by absorption lengths. Long distances r from a coil the magnetic

(near) field from a coil drops off as 1 /r 3 . At smaller distances, the electric and

magnetic fields can be expressed in terms of the vector magnetic potential, Page 22 16522060_1 (GHMatters) P108158.AU.1 which in turn can be expressed in closed form in terms of elliptic integrals of the first and second kind. The heating occurs only in a region that is comparable in size to the dimensions of the coil source itself. Accordingly, if it is desired to preferentially heat a region characterized by a radius, the source coil will be chosen to have a similar radius. The heating drops off very rapidly outside of a hemispherical region of radius because of the 1 /r 3 drop off of the magnetic field. Since it is proposed to use the radiofrequency the diseased tissue accessible only externally or from inner cavities, it is reasonable to consider a coil radii of between approximately 2 to 6 mm.

[Para 71] The radius of the source coil(s) as well as the number of ampere

turns (NI) in the source coils give the magnitude and spatial extent of the

magnetic field, and the radiofrequency is a factor that relates the magnitude of

the electric field to the magnitude of the magnetic field. The heating is

proportional to the product of the conductivity and the square of the electric

field. For target tissues of interest that are near external or internal surfaces,

the conductivity is that of skin and mucous tissue. The duty cycle of the pulse

train as well as the total train duration of a pulse train are factors which affect

how much total energy is delivered to the tissue.

[Para 72] Preferred parameters for a radiofrequency energy source have been

determined to be a coil radii between 2 and 6 mm, radiofrequencies in the

range of 3-6 MHz, total pulse train durations of 0.2 to 0.4 seconds, and a duty

cycle of between 2.5% and 5%. FIGS. 3-6 show how the number of ampere

turns varies as these parameters are varied in order to give a temperature rise

Page 23 16522060_1 (GHMatters) P108158.AU.1 that produces an Arrhenius integral of approximately one or unity for HSP activation. With reference to FIG. 3, for an RF frequency of 6 MHz, a pulse train duration of between 0.2 and 0.4 seconds, a coil radius between 0.2 and 0.6 cm, and a duty cycle of 5%, the peak ampere turns (NI) is 13 at the 0.6 cm coil radius and 20 at the 0.2 cm coil radius. For a 3 MHz frequency, as illustrated in

FIG. 4, the peak ampere turns is 26 when the pulse train duration is 0.4

seconds and the coil radius is 0.6 cm and the duty cycle is 5%. However, with

the same 5% duty cycle, the peak ampere turns is 40 when the coil radius is 0.2

cm and the pulse train duration is 0.2 seconds. A duty cycle of 2.5% is used in

FIGS. 5 and 6. This yields, as illustrated in FIG. 5, 18 amp turns for a 6 MHz

radiofrequency having a coil radius of 0.6 cm and a pulse train duration of 0.4

seconds, and 29 amp turns when the coil radius is only 0.2 cm and the pulse

train duration is 0.2 seconds. With reference to FIG. 6, with a duty cycle of 2.5%

and a radiofrequency of 3 MHz, the peak ampere turns is 36 when the pulse

train duration is 0.4 seconds and the coil radius is 0.6 cm, and 57 amp turns

when the pulse train duration is 0.2 seconds and the coil radius is 0.2 cm.

[Para 73] The time, in seconds, for the temperature rise to decay from

approximately 10°C to approximately 1C for coil radii between 0.2 cm and 0.6

cm is illustrated for a radiofrequency energy source in FIG. 7. The temperature

decay time is approximately 37 seconds when the radiofrequency coil radius is

0.2 cm, and approximately 233 seconds when the radiofrequency coil radius is

0.5 cm. When the radiofrequency coil radius is 0.6 cm, the decay time is

Page 24 16522060_1 (GHMatters) P108158.AU.1 approximately 336 seconds, which is still within the acceptable range of decay time, but at an upper range thereof.

[Para 74] Microwaves are another electromagnetic energy source which can

be utilized in accordance with the present invention. The frequency of the

microwave determines the tissue penetration distance. The gain of a conical

microwave horn is large compared to the microwave wavelength, indicating

under those circumstances that the energy is radiated mostly in a narrow

forward load. Typically, a microwave source used in accordance with the

present invention has a linear dimension on the order of a centimeter or less,

thus the source is smaller than the wavelength, in which case the microwave

source can be approximated as a dipole antenna. Such small microwave

sources are easier to insert into internal body cavities and can also be used to

radiate external surfaces. In that case, the heated region can be approximated

by a hemisphere with a radius equal to the absorption length of the microwave

in the body tissue being treated. As the microwaves are used to treat tissue

near external surfaces or surfaces accessible from internal cavities, frequencies

in the 10-20 GHz range are used, wherein the corresponding penetration

distances are only between approximately 2 and 4 mm.

[Para 75] The temperature rise of the tissue using a microwave energy source

is determined by the average power of the microwave and the total pulse train

duration. The duty cycle of the pulse train determines the peak power in a

single pulse in a train of pulses. As the radius of the source is taken to be less

than approximately 1 centimeter, and frequencies between 10 and 20 GHz are

Page 25 16522060_1 (GHMatters) P108158.AU.1 typically used, a resulting pulse train duration of 0.2 and 0.6 seconds is preferred.

[Para 76] The required power decreases monotonically as the train duration

increases and as the microwave frequency increases. For a frequency of 10

GHz, the average power is 18 watts when the pulse train duration is 0.6

seconds, and 52 watts when the pulse train duration is 0.2 seconds. For a 20

GHz microwave frequency, an average power of 8 watts is used when the pulse

train is 0.6 seconds, and can be 26 watts when the pulse train duration is only

0.2 seconds. The corresponding peak power are obtained from the average

power simply by dividing by the duty cycle.

[Para 77] With reference now to FIG. 8, a graph depicts the average

microwave power in watts of a microwave having a frequency of 10 GHz and a

pulse train duration from between 0.2 seconds and 0.6 seconds. FIG. 9 is a

similar graph, but showing the average microwave power for a microwave

having a frequency of 20 GHz. Thus, it will be seen that the average microwave

source power varies as the total train duration and microwave frequency vary.

The governing condition, however, is that the Arrhenius integral for HSP

activation in the heated region is approximately 1.

[Para 78] With reference to FIG. 10, a graph illustrates the time, in seconds,

for the temperature to decay from approximately 10°C to 1C compared to

microwave frequencies between 58 MHz and 20000 MHz. The minimum and

maximum temperature decay for the preferred range of microwave frequencies

Page 26 16522060_1 (GHMatters) P108158.AU.1 are 8 seconds when the microwave frequency is 20 GHz, and 16 seconds when the microwave frequency is 10 GHz.

[Para 79] Utilizing ultrasound as an energy source enables heating of surface

tissue, and tissues of varying depths in the body, including rather deep tissue.

The absorption length of ultrasound in the body is rather long, as evidenced by

its widespread use for imaging. Accordingly, ultrasound can be focused on

target regions deep within the body, with the heating of a focused ultrasound

beam concentrated mainly in the approximately cylindrical focal region of the

beam. The heated region has a volume determined by the focal waist of the

airy disc and the length of the focal waist region, that is the confocal

parameter. Multiple beams from sources at different angles can also be used,

the heating occurring at the overlapping focal regions.

[Para 80] For ultrasound, the relevant parameters for determining tissue

temperature are frequency of the ultrasound, total train duration, and

transducer power when the focal length and diameter of the ultrasound

transducer is given. The frequency, focal length, and diameter determine the

volume of the focal region where the ultrasound energy is concentrated. It is

the focal volume that comprises the target volume of tissue for treatment.

Transducers having a diameter of approximately 5 cm and having a focal length

of approximately 10 cm are readily available. Favorable focal dimensions are

achieved when the ultrasound frequency is between 1 and 5 MHz, and the total

train duration is 0.1 to 0.5 seconds. For example, for a focal length of 10 cm

Page 27 16522060_1 (GHMatters) P108158.AU.1 and the transducer diameter of 5 cm, the focal volumes are 0.02 cc at 5 MHz and 2.36 cc at 1 MHz.

[Para 81] With reference now to FIG. 11, a graph illustrates the average

source power in watts compared to the frequency (between 1 MHz and 5 MHz),

and the pulse train duration (between 0.1 and 0.5 seconds). A transducer focal

length of 10 cm and a source diameter of 5 cm have been assumed. The

required power to give the Arrhenius integral for HSP activation of

approximately 1 decreases monotonically as the frequency increases and as the

total train duration increases. Given the preferred parameters, the minimum

power for a frequency of 1 GHz and a pulse train duration of 0.5 seconds is

5.72 watts, whereas for the 1 GHz frequency and a pulse train duration of 0.1

seconds the maximum power is 28.6 watts. For a 5 GHz frequency, 0.046

watts is required for a pulse train duration of 0.5 seconds, wherein 0.23 watts

is required for a pulse train duration of 0.1 seconds. The corresponding peak

power during an individual pulse is obtained simply by dividing by the duty

cycle.

[Para 82] FIGURE 12 illustrates the time, in seconds, for the temperature to

diffuse or decay from 10°C to 6°C when the ultrasound frequency is between 1

and 5 MHz. FIG. 13 illustrates the time, in seconds, to decay from

approximately 10°C to approximately 1°C for ultrasound frequencies from 1 to

MHz. For the preferred focal length of 10 cm and the transducer diameter of

cm, the maximum time for temperature decay is 366 seconds when the

ultrasound frequency is 1 MHz, and the minimum temperature decay is 15

Page 28 16522060_1 (GHMatters) P108158.AU.1 seconds when the microwave frequency is 5 MHz. As the FDA only requires the temperature rise be less than 6°C for test times of minutes, the 366 second decay time at 1 MHz to get to a rise of1C over the several minutes is allowable. As can be seen in FIGS. 12 and 13, the decay times to a rise of 6°C are much smaller, by a factor of approximately 70, than that of1°C.

[Para 83] FIGURE 14 illustrates the volume of focal heated region, in cubic

centimeters, as compared to ultrasound frequencies from between 1 and 5

MHz. Considering ultrasound frequencies in the range of 1 to 5 MHz, the

corresponding focal sizes for these frequencies range from 3.7 mm to 0.6 mm,

and the length of the focal region ranges from 5.6 cm to 1.2 cm. The

corresponding treatment volumes range from between approximately 2.4 cc

and 0.02 cc.

[Para 84] Examples of parameters giving a desired HSP activation Arrhenius

integral greater than 1 and damage Arrhenius integral less than 1 is a total

ultrasound power between 5.8-17 watts, a pulse duration of 0.5 seconds, an

interval between pulses of 5 seconds, with total number of pulses 10 within the

total pulse stream time of 50 seconds. The target treatment volume would be

approximately 1 mm on a side. Larger treatment volumes could be treatable by

an ultrasound system similar to a laser diffracted optical system, by applying

ultrasound in multiple simultaneously applied adjacent but separated and

spaced columns. The multiple focused ultrasound beams converge on a very

small treatment target within the body, the convergence allowing for a minimal

heating except at the overlapping beams at the target. This area would be

Page 29 16522060_1 (GHMatters) P108158.AU.1 heated and stimulate the activation of HSPs and facilitate protein repair by transient high temperature spikes. However, given the pulsating aspect of the invention as well as the relatively small area being treated at any given time, the treatment is in compliance with FDA/FCC requirements for long term (minutes) average temperature rise <1K. An important distinction of the invention from existing therapeutic heating treatments for pain and muscle strain is that there are no high T spikes in existing techniques, and these are required for efficiently activating HSPs and facilitating protein repair to provide healing at the cellular level.

[Para 85] The pulse train mode of energy delivery has a distinct advantage

over a single pulse or gradual mode of energy delivery, as far as the activation

of remedial HSPs and the facilitation of protein repair is concerned. There are

two considerations that enter into this advantage:

[Para 86] First, a big advantage for HSP activation and protein repair in an

SDM energy delivery mode comes from producing a spike temperature of the

order of 10°C. This large rise in temperature has a big impact on the Arrhenius

integrals that describe quantitatively the number of HSPs that are activated and

the rate of water diffusion into the proteins that facilitates protein repair. This

is because the temperature enters into an exponential that has a big

amplification effect.

[Para 87] It is important that the temperature rise not remain at the high

value (10°C or more) for long, because then it would violate the FDA and FCC

Page 30 16522060_1 (GHMatters) P108158.AU.1 requirements that over periods of minutes the average temperature rise must be less than 1°C (or in the case of ultrasound 6°C).

[Para 88] An SDM mode of energy delivery uniquely satisfies both of these

foregoing considerations byjudicious choice of the power, pulse time, pulse

interval, and the volume of the target region to be treated. The volume of the

treatment region enters because the temperature must decay from its high

value of the order of 10°C fairly rapidly in order for the long term average

temperature rise not to exceed the long term FDA/FCC limit of 6°C for

ultrasound frequencies and 1°C or less for electromagnetic radiation energy

sources.

[Para 89] For a region of linear dimension L, the time that it takes the peak

temperature to e-fold in tissue is roughly L 2 /16D, where D = 0.00143 cm 2 /sec

is the typical heat diffusion coefficient. For example, if L = 1 mm, the decay

time is roughly 0.4 sec. Accordingly, for a region 1 mm on a side, a train

consisting of 10 pulses each of duration 0.5 seconds, with an interval between

pulses of 5 second can achieve the desired momentary high rise in temperature

while still not exceeding an average long term temperature rise of1C. This is

demonstrated further below.

[Para 90] The limitation of heated volume is the reason why RF

electromagnetic radiation is not as good of a choice for SDM-type treatment of

regions deep with the body as ultrasound. The long skin depths (penetration

distances) and Ohmic heating all along the skin depth results in a large heated

volume whose thermal inertia does not allow both the attainment of a high

Page 31 16522060_1 (GHMatters) P108158.AU.1 spike temperature that activates HSPs and facilitates protein repair, and the rapid temperature decay that satisfies the long term FDA and FCC limit on average temperature rise.

[Para91] Ultrasound has already been used to therapeutically heat regions of

the body to ease pain and muscle strain. However, the heating has not

followed the SDM-type protocol and does not have the temperature spikes that

are responsible for the excitation of HSPs.

[Para92] Consider, then, a group of focused ultrasound beams that are

directed at a target region deep within the body. To simplify the mathematics,

suppose that the beams are replaced by a single source with a spherical surface

shape that is focused on the center of the sphere. The absorption lengths of

ultrasound can be fairly long. Table 3 below shows typical absorption

coefficients for ultrasound at 1 MHz. The absorption coefficients are roughly

proportional to the frequency.

[Para93] Table 3. Typical absorption coefficients for 1 MHz ultrasound in

body tissue:

Body Tissue Attenuation Coefficient at 1 MHz (cm-1)

Water 0.00046

Blood 0.0415

Fat 0.145

Liver 0.115-0.217

Kidney 0.23

Muscle 0.3-0.76

Page 32 16522060_1 (GHMatters) P108158.AU.1

Bone 1.15

[Para94] Assuming that the geometric variation of the incoming radiation

due to the focusing dominates any variation due to attenuation, the intensity of

the incoming ultrasound at a distance r from the focus can be written

approximately as:

I(r) = P/(4rrr 2) [1]

where P denotes the total ultrasound power.

The temperature rise at the end of a short pulse of duration tp at r is then

dT(tp) = Patp / (4rrCyr 2) [2]

where a is the absorption coefficient and Cv is the specific volume heat

capacity. This will be the case until the r is reached at which the heat diffusion

length at tp becomes comparable to r, or the diffraction limit of the focused

beam is reached. For smaller r, the temperature rise is essentially independent

of r. As an example, suppose the diffraction limit is reached at a radial distance

that is smaller than that determined by heat diffusion. Then

rdif = (4Dtp) 1/2 [3]

where D is the heat diffusion coefficient, and for r<rdif, the temperature rise at

tp is

dT(rdif, tp) = 3Pa/(8rrCvD) when r< rdif [4]

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

dTp(r) = {Patp/(4rrCy}[(6/rdif 2)U{rdif-r) -(I /r 2 )U(r-rdif)] [5]

On applying the Green's function for the heat diffusion equation,

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

Page 33 16522060_1 (GHMatters) P108158.AU.1 to this initial temperature distribution, we find that the temperature dT(t) at the focal point r=O at a time t is dT(t) = [dTo/{(1 /2)+(rl /2/6)}][(1/2)(tp/t) 3 2 / + (rrl/ 2/6)(tp/t)] [7] with dTo = 3Poa/(8rrCvD) [8]

[Para95] A good approximation to eq. [7] is provided by:

dT(t) ~z dTo (tp /t) 3/2 [9]

as can be seen in FIG. 15, which is a comparison of eqs. [7] and [9] for dT(t)/

dTo at the target treatment zone. The bottom curve is the approximate

expression of eq [9].

The Arrhenius integral for a train of N pulses can now be evaluated with the

temperature rise given by eq. [9]. In this expression,

dTN(t) = dT(t-nti) [11]

where dT(t-nti) is the expression of eq. [9] with t replaced by t-ntrand with ti

designating the interval between pulses.

[Para 96] The Arrhenius integral can be evaluated approximately by dividing the

integration interval into the portion where the temperature spikes occur and the

portion where the temperature spike is absent. The summation over the

temperature spike contribution can be simplified by applying Laplace's end

point formula to the integral over the temperature spike. In addition, the

integral over the portion when the spikes are absent can be simplified by noting

that the non-spike temperature rise very rapidly reaches an asymptotic value,

Page 34 16522060_1 (GHMatters) P108158.AU.1 so that a good approximation is obtained by replacing the varying time rise by its asymptotic value. When these approximations are made, eq. [10] becomes:

Q = AN[{tp(2kBT 2 /(3EdTo)}exp[-(E/kB)1 /(To + dTo+ dTN(Nti))]

+exp[-(E/kB)1 /(To + dTN(Nti))]] [12]

where

dTN(Nti) ~ 2.5 dTo (tp/t) 3 / 2 [13]

(The 2.5 in eq. [13] arises from the summation over n of (N-n)- 3 / 2 and is the

magnitude of the harmonic number (N,3/2) for typical N of interest.)

[Para97]It is interesting to compare this expression with that for SDM applied

to the retina. The first term is very similar to that from the spike contribution

in the retina case, except that the effective spike interval is reduced by a factor

of 3 for this 3D converging beam case. The second term, involving dTN(Nti) is

much smaller than in the retina case. There the background temperature rise

was comparable in magnitude to the spike temperature rise. But here in the

converging beam case, the background temperature rise is much smaller by the

ratio (tp/t) 3 / 2 . This points up the importance of the spike contribution to the

activation or production of HSP's and the facilitation of protein repair, as the

background temperature rise which is similar to the rise in a continuous

ultrasound heating case is insignificant compared to the spike contribution. At

the end of the pulse train, even this low background temperature rise rapidly

disappears by heat diffusion.

[Para98] FIGURES 16 and 17 show the magnitude of the logarithm of the

Arrhenius integrals for damage and for HSP activation or production as a

Page 35 16522060_1 (GHMatters) P108158.AU.1 function of dTo for a pulse duration tp = 0.5 sec, pulse interval ti = 10 sec, and total number of pulses N = 10. Logarithm of Arrhenius integrals [eq. 12] for damage and for HSP activation as a function of the temperature rise in degrees

Kelvin from a single pulse dTo, for a pulse duration tp = 0.5 sec., pulse interval

ti = 10 sec., and a total number of ultrasound pulses N = 10. FIG. 16 shows

the logarithm of the damage integral with the Arrhenius constants A =

8.71 x1033 sec-1 and E = 3.55x10-12 ergs. FIG. 17 shows the logarithm of the

HSP activation integral with the Arrhenius constants A = 1.24x1027 sec- 1 and E

= 2.66x10-12 ergs. The graphs in FIGS. 16 and 17 show that Odamage does not

exceed 1 until dTo exceeds 11.3 K, whereas Qhsp is greater than 1 over the

whole interval shown, the desired condition for cellular repair without damage.

[Para 99] Equation [8] shows that when a = 0.1 cm- 1, a dTo of 11.5 K can be

achieved with a total ultrasound power of 5.8 watts. This is easily achievable.

If a is increased by a factor of 2 or 3, the resulting power is still easily

achievable. The volume of the region where the temperature rise is constant

(i.e. the volume corresponding to r=rd = (4Dtp) 1/ 2 ) is 0.00064 cc. This

corresponds to a cube that is 0.86 mm on a side.

[Para100] This simple example demonstrates that focused ultrasound should

be usable to stimulate reparative HSP's deep in the body with easily attainable

equipment:

Total ultrasound power: 5.8 watts - 17 watts

Pulse time 0.5 sec

Pulse interval 5 sec

Page 36 16522060_1 (GHMatters) P108158.AU.1

Total train duration (N=10) 50 sec

To expedite the treatment of larger internal volumes, a SAPRA system can be

used.

[Para101] The pulsed energy source may be directed to an exterior of a body

which is adjacent to the target tissue or has a blood supply close to the surface

of the exterior of the body. Alternatively, a device may be inserted into a cavity

of a body to apply the pulsed energy source to the target tissue. Whether the

energy source is applied outside of the body or inside of the body and what

type of device is utilized depends upon the energy source selected and used to

treat the target tissue.

[Para 102] Photostimulation, in accordance with the present invention, can be

effectively transmitted to an internal surface area or tissue of the body utilizing

an endoscope, such as a bronchoscope, proctoscope, colonoscope or the like.

Each of these consist essentially of a flexible tube that itself contains one or

more internal tubes. Typically, one of the internal tubes comprises a light pipe

or multi-mode optical fiber which conducts light down the scope to illuminate

the region of interest and enable the doctor to see what is at the illuminated

end. Another internal tube could consist of wires that carry an electrical current

to enable the doctor to cauterize the illuminated tissue. Yet another internal

tube might consist of a biopsy tool that would enable the doctor to snip off and

hold on to any of the illuminated tissue.

[Para 103] In the present invention, one of these internal tubes is used as an

electromagnetic radiation pipe, such as a multi-mode optical fiber, to transmit

Page 37 16522060_1 (GHMatters) P108158.AU.1 the SDM or other electromagnetic radiation pulses that are fed into the scope at the end that the doctor holds. With reference now to FIG. 18, a light generating unit 10, such as a laser having a desired wavelength and/or frequency is used to generate electromagnetic radiation, such as laser light, in a controlled, pulsed manner to be delivered through a light tube or pipe 12 to a distal end of the scope 14, illustrated in FIG. 19, which is inserted into the body and the laser light or other radiation 16 delivered to the target tissue 18 to be treated.

[Para 104] With reference now to FIG. 20, a schematic diagram is shown of a

system for generating electromagnetic energy radiation, such as laser light,

including SDM. The system, generally referred to by the reference number 20,

includes a laser console 22, such as for example the 810 nm near infrared

micropulsed diode laser in the preferred embodiment. The laser generates a

laser light beam which is passed through optics, such as an optical lens or

mask, or a plurality of optical lenses and/or masks 24 as needed. The laser

projector optics 24 pass the shaped light beam to a delivery device 26, such as

an endoscope, for projecting the laser beam light onto the target tissue of the

patient. It will be understood that the box labeled 26 can represent both the

laser beam projector or delivery device as well as a viewing system/camera,

such as an endoscope, or comprise two different components in use. The

viewing system/camera 26 provides feedback to a display monitor 28, which

may also include the necessary computerized hardware, data input and

controls, etc. for manipulating the laser 22, the optics 24, and/or the

projection/viewing components 26.

Page 38 16522060_1 (GHMatters) P108158.AU.1

[Para 105] With reference now to FIG. 21, in one embodiment, the laser light

beam 30 may be passed through a collimator lens 32 and then through a mask

34. In a particularly preferred embodiment, the mask 34 comprises a

diffraction grating. The mask/diffraction grating 34 produces a geometric

object, or more typically a geometric pattern of simultaneously produced

multiple laser spots or other geometric objects. This is represented by the

multiple laser light beams labeled with reference number 36. Alternatively, the

multiple laser spots may be generated by a plurality of fiber optic waveguides.

Either method of generating laser spots allows for the creation of a very large

number of laser spots simultaneously over a very wide treatment field. In fact,

a very high number of laser spots, perhaps numbering in the hundreds even

thousands or more could be simultaneously generated to cover a given area of

the target tissue, or possibly even the entirety of the target tissue. A wide array

of simultaneously applied small separated laser spot applications may be

desirable as such avoids certain disadvantages and treatment risks known to be

associated with large laser spot applications.

[Para 106] Using optical features with a feature size on par with the

wavelength of the laser employed, for example using a diffraction grating, it is

possible to take advantage of quantum mechanical effects which permits

simultaneous application of a very large number of laser spots for a very large

target area. The individual spots produced by such diffraction gratings are all

of a similar optical geometry to the input beam, with minimal power variation

for each spot. The result is a plurality of laser spots with adequate irradiance to

Page 39 16522060_1 (GHMatters) P108158.AU.1 produce harmless yet effective treatment application, simultaneously over a large target area. The present invention also contemplates the use of other geometric objects and patterns generated by other diffractive optical elements.

[Para 107] The laser light passing through the mask 34 diffracts, producing a

periodic pattern a distance away from the mask 34, shown by the laser beams

labeled 36 in FIG. 21. The single laser beam 30 has thus been formed into

hundreds or even thousands of individual laser beams 36 so as to create the

desired pattern of spots or other geometric objects. These laser beams 36 may

be passed through additional lenses, collimators, etc. 38 and 40 in order to

convey the laser beams and form the desired pattern. Such additional lenses,

collimators, etc. 38 and 40 can further transform and redirect the laser beams

36 as needed.

[Para 108] Arbitrary patterns can be constructed by controlling the shape,

spacing and pattern of the optical mask 34. The pattern and exposure spots

can be created and modified arbitrarily as desired according to application

requirements by experts in the field of optical engineering. Photolithographic

techniques, especially those developed in the field of semiconductor

manufacturing, can be used to create the simultaneous geometric pattern of

spots or other objects.

[Para 109] FIG. 22 illustrates diagrammatically a system which couples

multiple light sources into the pattern-generating optical subassembly

described above. Specifically, this system 20' is similar to the system 20

described in FIG. 20 above. The primary differences between the alternate

Page 40 16522060_1 (GHMatters) P108158.AU.1 system 20' and the earlier described system 20 is the inclusion of a plurality of laser consoles, the outputs of which are each fed into a fiber coupler 42. The fiber coupler produces a single output that is passed into the laser projector optics 24 as described in the earlier system. The coupling of the plurality of laser consoles 22 into a single optical fiber is achieved with a fiber coupler 42 as is known in the art. Other known mechanisms for combining multiple light sources are available and may be used to replace the fiber coupler described herein.

[Para 110] In this system 20' the multiple light sources 22 follow a similar

path as described in the earlier system 20, i.e., collimated, diffracted,

recollimated, and directed to the projector device and/or tissue. In this

alternate system 20' the diffractive element must function differently than

described earlier depending upon the wavelength of light passing through,

which results in a slightly varying pattern. The variation is linear with the

wavelength of the light source being diffracted. In general, the difference in the

diffraction angles is small enough that the different, overlapping patterns may

be directed along the same optical path through the projector device 26 to the

tissue for treatment.

[Para 111] Since the resulting pattern will vary slightly for each wavelength, a

sequential offsetting to achieve complete coverage will be different for each

wavelength. This sequential offsetting can be accomplished in two modes. In

the first mode, all wavelengths of light are applied simultaneously without

identical coverage. An offsetting steering pattern to achieve complete coverage

Page 41 16522060_1 (GHMatters) P108158.AU.1 for one of the multiple wavelengths is used. Thus, while the light of the selected wavelength achieves complete coverage of the tissue, the application of the other wavelengths achieves either incomplete or overlapping coverage of the tissue. The second mode sequentially applies each light source of a varying wavelength with the proper steering pattern to achieve complete coverage of the tissue for that particular wavelength. This mode excludes the possibility of simultaneous treatment using multiple wavelengths, but allows the optical method to achieve identical coverage for each wavelength. This avoids either incomplete or overlapping coverage for any of the optical wavelengths.

[Para112] These modes may also be mixed and matched. For example, two

wavelengths may be applied simultaneously with one wavelength achieving

complete coverage and the other achieving incomplete or overlapping coverage,

followed by a third wavelength applied sequentially and achieving complete

coverage.

[Para 113] FIG. 23 illustrates diagrammatically yet another alternate

embodiment of the inventive system 20". This system 20" is configured

generally the same as the system 20 depicted in FIG. 20. The main difference

resides in the inclusion of multiple pattern-generating subassembly channels

tuned to a specific wavelength of the light source. Multiple laser consoles 22

are arranged in parallel with each one leading directly into its own laser

projector optics 24. The laser projector optics of each channel 44a, 44b, 44c

comprise a collimator 32, mask or diffraction grating 34 and recollimators 38,

as described in connection with FIG. 21 above - the entire set of optics

Page 42 16522060_1 (GHMatters) P108158.AU.1 tuned for the specific wavelength generated by the corresponding laser console

22. The output from each set of optics 24 is then directed to a beam splitter

46 for combination with the other wavelengths. It is known by those skilled in

the art that a beam splitter used in reverse can be used to combine multiple

beams of light into a single output. The combined channel output from the

final beam splitter 46c is then directed through the projector device 26.

[Para 114] In this system 20" the optical elements for each channel are tuned

to produce the exact specified pattern for that channel's wavelength.

Consequently, when all channels are combined and properly aligned a single

steering pattern may be used to achieve complete coverage of the tissue for all

wavelengths.

[Para 115] The system 20" may use as many channels 44a, 44b, 44c, etc. and

beam splitters 46a, 46b, 46c, etc. as there are wavelengths of light being used

in the treatment.

[Para 116] Implementation of the system 20" may take advantage of different

symmetries to reduce the number of alignment constraints. For example, the

proposed grid patterns are periodic in two dimensions and steered in two

dimensions to achieve complete coverage. As a result, if the patterns for each

channel are identical as specified, the actual pattern of each channel would not

need to be aligned for the same steering pattern to achieve complete coverage

for all wavelengths. Each channel would only need to be aligned optically to

achieve an efficient combination.

Page 43 16522060_1 (GHMatters) P108158.AU.1

[Para 117] In system 20", each channel begins with a light source 22, which

could be from an optical fiber as in other embodiments of the pattern

generating subassembly. This light source 22 is directed to the optical

assembly 24 for collimation, diffraction, recollimation and directed into the

beam splitter which combines the channel with the main output.

[Para 118] It will be understood that the laser light generating systems

illustrated in FIGS. 20-23 are exemplary. Other devices and systems can be

utilized to generate a source of SDM laser light which can be operably passed

through to a projector device, typically in the form of an endoscope having a

light pipe or the like. Other forms of electromagnetic radiation may also be

generated and used, including ultraviolet waves, microwaves, other

radiofrequency waves, and laser light at predetermined wavelengths. Moreover,

ultrasound waves may also be generated and used to create a thermal time

course temperature spike in the target tissue sufficient to activate or produce

heat shock proteins in the cells of the target tissue without damaging the target

tissue itself. In order to do so, typically, a pulsed source of ultrasound or

electromagnetic radiation energy is provided and applied to the target tissue in

a manner which raises the target tissue temperature, such as between 6°C and

11°C, transiently while only 6°C or 1C or less for the long term, such as over

several minutes.

[Para 119] For deep tissue that is not near an internal orifice, a light pipe is

not an effective means of delivering the pulsed energy. In that case, pulsed low

Page 44 16522060_1 (GHMatters) P108158.AU.1 frequency electromagnetic energy or preferably pulsed ultrasound can be used to cause a series of temperature spikes in the target tissue.

[Para 120] Thus, in accordance with the present invention, a source of pulsed

ultrasound or electromagnetic radiation is applied to the target tissue in order

to stimulate HSP production or activation and to facilitate protein repair in the

living animal tissue. In general, electromagnetic radiation may be ultraviolet

waves, microwaves, other radiofrequency waves, laser light at predetermined

wavelengths, etc. On the other hand, if electromagnetic energy is to be used

for deep tissue targets away from natural orifices, absorption lengths restrict

the wavelengths to those of microwaves or radiofrequency waves, depending on

the depth of the target tissue. However, ultrasound is to be preferred to long

wavelength electromagnetic radiation for deep tissue targets away from natural

orifices.

[Para 121] The ultrasound or electromagnetic radiation is pulsed so as to

create a thermal time-course in the tissue that stimulates HSP production or

activation and facilitates protein repair without causing damage to the cells and

tissue being treated. The area and/or volume of the treated tissue is also

controlled and minimized so that the temperature spikes are on the order of

several degrees, e.g. approximately 10°C, while maintaining the long-term rise

in temperature to be less than the FDA mandated limit, such as 1°C. It has been

found that if too large of an area or volume of tissue is treated, the increased

temperature of the tissue cannot be diffused sufficiently quickly enough to

meet the FDA requirements. However, limiting the area and/or volume of the

Page 45 16522060_1 (GHMatters) P108158.AU.1 treated tissue as well as creating a pulsed source of energy accomplishes the goals of the present invention of stimulating HSP activation or production by heating or otherwise stressing the cells and tissue, while allowing the treated cells and tissues to dissipate any excess heat generated to within acceptable limits.

[Para 122] It is believed that stimulating HSP production in accordance with

the present invention can be effectively utilized in treating a wide array of

tissue abnormalities, ailments, and even infections. For example, the viruses

that cause colds primarily affect a small port of the respiratory epithelium in the

nasal passages and nasopharynx. Similar to the retina, the respiratory

epithelium is a thin and clear tissue. With reference to FIG. 24, a cross

sectional view of a human head 48 is shown with an endoscope 14 inserted into

the nasal cavity 50 and energy 16, such as laser light or the like, being directed

to tissue 18 to be treated within the nasal cavity 50. The tissue 18 to be

treated could be within the nasal cavity 50, including the nasal passages, and

nasopharynx.

[Para 123] To assure absorption of the laser energy, or other energy source,

the wavelength can be adjusted to an infrared (IR) absorption peak of water, or

an adjuvant dye can be used to serve as a photosensitizer. In such a case,

treatment would then consist of drinking, or topically applying, the adjuvant,

waiting a few minutes for the adjuvant to permeate the surface tissue, and then

administering the laser light or other energy source 16 to the target tissue 18

for a few seconds, such as via optical fibers in an endoscope 14, as illustrated

Page 46 16522060_1 (GHMatters) P108158.AU.1 in FIG. 24. To provide comfort of the patient, the endoscope 14 could be inserted after application of a topical anesthetic. If necessary, the procedure could be repeated periodically, such as in a day or so.

[Para 124] The treatment would stimulate the activation or production of heat

shock proteins and facilitate protein repair without damaging the cells and

tissues being treated. As discussed above, certain heat shock proteins have

been found to play an important role in the immune response as well as the

well-being of the targeted cells and tissue. The source of energy could be

monochromatic laser light, such as 810 nm wavelength laser light,

administered in a manner similar to that described in the above-referenced

patent applications, but administered through an endoscope or the like, as

illustrated in FIG. 24. The adjuvant dye would be selected so as to increase the

laser light absorption. While this comprises a particularly preferred method and

embodiment of performing the invention, it will be appreciated that other types

of energy and delivery means could be used to achieve the same objectives in

accordance with the present invention.

[Para 125] With reference now to FIG. 25, a similar situation exists for the flu

virus, where the primary target is the epithelium of the upper respiratory tree,

in segments that have diameters greater than about 3.3 mm, namely, the upper

six generations of the upper respiratory tree. A thin layer of mucous separates

the targeted epithelial cells from the airway lumen, and it is in this layer that

the antigen-antibody interactions occur that result in inactivation of the virus.

Page 47 16522060_1 (GHMatters) P108158.AU.1

[Para 126] With continuing reference to FIG. 25, the flexible light tube 12 of a

bronchoscope 14 is inserted through the individual's mouth 52 through the

throat and trachea 54 and into a bronchus 56 of the respiratory tree. There the

laser light or other energy source 16 is administered and delivered to the tissue

in this area of the uppermost segments to treat the tissue and area in the same

manner described above with respect to FIG. 24. It is contemplated that a

wavelength of laser or other energy would be selected so as to match an IR

absorption peak of the water resident in the mucous to heat the tissue and

stimulate HSP activation or production and facilitate protein repair, with its

attendant benefits.

[Para 127] With reference now to FIG. 26, a colonoscope 14 could have

flexible optical tube 12 thereof inserted into the anus and rectum 58 and into

either the large intestine 60 or small intestine 62 so as to deliver the selected

laser light or other energy source 16 to the area and tissue to be treated, as

illustrated. This could be used to assist in treating colon cancer as well as

other gastrointestinal issues.

[Para 128] Typically, the procedure could be performed similar to a

colonoscopy in that the bowel would be cleared of all stool, and the patient

would lie on his/her side and the physician would insert the long, thin light

tube portion 12 of the colonoscope 14 into the rectum and move it into the

area of the colon, large intestine 60 or small intestine 64 to the area to be

treated. The physician could view through a monitor the pathway of the

inserted flexible member 12 and even view the tissue at the tip of the

Page 48 16522060_1 (GHMatters) P108158.AU.1 colonoscope 14 within the intestine, so as to view the area to be treated. Using one of the other fiber optic or light tubes, the tip 64 of the scope would be directed to the tissue to be treated and the source of laser light or other radiation 16 would be delivered through one of the light tubes of the colonoscope 14 to treat the area of tissue to be treated, as described above, in order to stimulate HSP activation or production in that tissue 18.

[Para 129] With reference now to FIG. 27, another example in which the

present invention can be advantageously used is what is frequently referred to

as "leaky gut" syndrome, a condition of the gastrointestinal (GI) tract marked by

inflammation and other metabolic dysfunction. Since the GI tract is susceptible

to metabolic dysfunction similar to the retina, it is anticipated that it will

respond well to the treatment of the present invention. This could be done by

means of subthreshold, diode micropulse laser (SDM) treatment, as discussed

above, or by other energy sources and means as discussed herein and known in

the art.

[Para 130] With continuing reference to FIG. 27, the flexible light tube 12 of

an endoscope or the like is inserted through the patient's mouth 52 through

the throat and trachea area 54 and into the stomach 66, where the tip or end

64 thereof is directed towards the tissue 18 to be treated, and the laser light or

other energy source 16 is directed to the tissue 18. It will be appreciated by

those skilled in the art that a colonoscope could also be used and inserted

through the rectum 58 and into the stomach 66 or any tissue between the

stomach and the rectum.

Page 49 16522060_1 (GHMatters) P108158.AU.1

[Para 131] If necessary, a chromophore pigment could be delivered to the GI

tissue orally to enable absorption of the radiation. If, for instance, unfocused

810 nm radiation from a laser diode or LED were to be used, the pigment would

have an absorption peak at or near 810 nm. Alternatively, the wavelength of

the energy source could be adjusted to a slightly longer wavelength at an

absorption peak of water, so that no externally applied chromophore would be

required.

[Para 132] It is also contemplated by the present invention that a capsule

endoscope 68, such as that illustrated in FIG. 28, could be used to administer

the radiation and energy source in accordance with the present invention. Such

capsules are relatively small in size, such as approximately one inch in length,

so as to be swallowed by the patient. As the capsule or pill 68 is swallowed and

enters into the stomach and passes through the GI tract, when at the

appropriate location, the capsule or pill 68 could receive power and signals,

such as via antenna 70, so as to activate the source of energy 72, such as a

laser diode and related circuitry, with an appropriate lens 74 focusing the

generated laser light or radiation through a radiation-transparent cover 76 and

onto the tissue to be treated. It will be understood that the location of the

capsule endoscope 68 could be determined by a variety of means such as

external imaging, signal tracking, or even by means of a miniature camera with

lights through which the doctor would view images of the GI tract through

which the pill or capsule 68 was passing through at the time. The capsule or

pill 68 could be supplied with its own power source, such as by virtue of a

Page 50 16522060_1 (GHMatters) P108158.AU.1 battery, or could be powered externally via an antenna, such that the laser diode 72 or other energy generating source create the desired wavelength and pulsed energy source to treat the tissue and area to be treated.

[Para 133] As in the treatment of the retina in previous applications, the

radiation would be pulsed to take advantage of the micropulse temperature

spikes and associated safety, and the power could be adjusted so that the

treatment would be completely harmless to the tissue. This could involve

adjusting the peak power, pulse times, and repetition rate to give spike

temperature rises on the order of 10°C, while maintaining the long term rise in

temperature to be less than the FDA mandated limit of 1°C. If the pill form 68

of delivery is used, the device could be powered by a small rechargeable battery

or over wireless inductive excitation or the like. The heated/stressed tissue

would stimulate activation or production of HSP and facilitate protein repair,

and the attendant benefits thereof.

[Para 134] From the foregoing examples, the technique of the present

invention is limited to the treatment of conditions at near body surfaces or at

internal surfaces easily accessible by means of fiber optics or other optical

delivery means. The reason that the application of SDM to activate HSP activity

is limited to near surface or optically accessibly regions of the body is that the

absorption length of IR or visible radiation in the body is very short. However,

there are conditions deeper within tissue or the body which could benefit from

the present invention. Thus, the present invention contemplates the use of

ultrasound and/or radio frequency (RF) and even shorter wavelength

Page 51 16522060_1 (GHMatters) P108158.AU.1 electromagnetic (EM) radiation such as microwave which have relatively long absorption lengths in body tissue. The use of pulsed ultrasound is preferable to RF electromagnetic radiation to activate remedial HSP activity in abnormal tissue that is inaccessible to surface SDM or the like. Pulsed ultrasound sources can also be used for abnormalities at or near surfaces as well.

[Para 135] With reference now to FIG. 29, with ultrasound, a specific region

deep in the body can be specifically targeted by using one or more beams that

are each focused on the target site. The pulsating heating will then be largely

only in the targeted region where the beams are focused and overlap.

[Para 136] As illustrated in FIG. 29, an ultrasound transducer 78 or the like

generates a plurality of ultrasound beams 80 which are coupled to the skin via

an acoustic-impedance-matching gel, and penetrate through the skin 82 and

through undamaged tissue in front of the focus of the beams 80 to a target

organ 84, such as the illustrated liver, and specifically to a target tissue 86 to

be treated where the ultrasound beams 80 are focused. As mentioned above,

the pulsating heating will then only be at the targeted, focused region 86 where

the focused beams 80 overlap. The tissue in front of and behind the focused

region 86 will not be heated or affected appreciably.

[Para 137] The present invention contemplates not only the treatment of

surface or near surface tissue, such as using the laser light or the like, deep

tissue using, for example, focused ultrasound beams or the like, but also

treatment of blood diseases, such as sepsis. As indicated above, focused

ultrasound treatment could be used both at surface as well as deep body tissue,

Page 52 16522060_1 (GHMatters) P108158.AU.1 and could also be applied in this case in treating blood. However, it is also contemplated that the SDM and similar treatment options which are typically limited to surface or near surface treatment of epithelial cells and the like be used in treating blood diseases at areas where the blood is accessible through a relatively thin layer of tissue, such as the earlobe.

[Para 138] With reference now to FIGS. 30 and 31, treatment of blood

disorders simply requires the transmission of SDM or other electromagnetic

radiation or ultrasound pulses to the earlobe 88, where the SDM or other

radiation source of energy could pass through the earlobe tissue and into the

blood which passes through the earlobe. It would be appreciated that this

approach could also take place at other areas of the body where the blood flow

is relatively high and/or near the tissue surface, such as fingertips, inside of the

mouth or throat, etc.

[Para 139] With reference again to FIGS. 30 and 31, an earlobe 88 is shown

adjacent to a clamp device 90 configured to transmit SDM radiation or the like.

This could be, for example, by means of one or more laser diodes 92 which

would transmit the desired frequency at the desired pulse and pulse train to the

earlobe 88. Power could be provided, for example, by means of a lamp drive

94. Alternatively, the lamp drive 94 could be the actual source of laser light,

which would be transmitted through the appropriate optics and electronics to

the earlobe 88. The clamp device 90 would merely be used to clamp onto the

patient's earlobe and cause that the radiation be constrained to the patient's

earlobe 88. This may be by means of mirrors, reflectors, diffusers, etc. This

Page 53 16522060_1 (GHMatters) P108158.AU.1 could be controlled by a control computer 96, which would be operated by a keyboard 98 or the like. The system may also include a display and speakers

100, if needed, for example if the procedure were to be performed by an

operator at a distance from the patient.

[Para 140] The proposed treatment with a train of electromagnetic or

ultrasound pulses has two major advantages over earlier treatments that

incorporate a single short or sustained (long) pulse. First, the short (preferably

subsecond) individual pulses in the train activate cellular reset mechanisms like

HSP activation with larger reaction rate constants than those operating at longer

(minute or hour) time scales. Secondly, the repeated pulses in the treatment

provide large thermal spikes (on the order of 10,000) that allow the cell's repair

system to more rapidly surmount the activation energy barrier that separates a

dysfunctional cellular state from the desired functional state. The net result is a

"lowered therapeutic threshold" in the sense that a lower applied average power

and total applied energy can be used to achieve the desired treatment goal.

[Para 141] Although several embodiments have been described in detail

for purposes of illustration, various modifications may be made without

departing from the scope and spirit of the invention. Accordingly, the invention

is not to be limited, except as by the appended claims.

[Para142] It is to be understood that, if any prior art publication is

referred to herein, such reference does not constitute an admission that the

publication forms a part of the common general knowledge in the art, in

Australia or any other country.

Page 54 16522060_1 (GHMatters) P108158.AU.1

[Para143] In the claims which follow and in the preceding description of

the invention, except where the context requires otherwise due to express

language or necessary implication, the word "comprise" or variations such as

"comprises" or "comprising" is used in an inclusive sense, i.e. to specify the

presence of the stated features but not to preclude the presence or addition of

further features in various embodiments of the invention.

Page 55 16522060_1 (GHMatters) P108158.AU.1

Claims (15)

1. A system adapted to heat treat biological tissues, comprising:

a pulsed energy source having energy parameters including wavelength

or frequency, power and a duty cycle of 10% or less that raises a target tissue

temperature between approximately six and eleven degrees Celsius at least

during application of the pulsed energy source to the target tissue for a pulsed

train duration of less than one second, wherein the average temperature rise of

the tissue over six minutes or less is maintained at or below six degrees Celsius

so as to not permanently damage the target tissue.

2. The system of claim 1, wherein the pulsed energy source stimulates heat

shock protein activation in the target tissue.

3. The system of claim 1 or claim 2, wherein the average temperature rise of

the target tissue is maintained at approximately one degree Celsius or less over

six minutes or less.

4. The system of any one of claims 1 to 3, wherein the pulsed energy source

energy parameters are selected so that approximately 20 to 40 joules of energy

is absorbed by each cubic centimeter of the target tissue.

5. The system of any one of claims 1 to 4, including a device insertable into

a cavity of a body to apply the pulsed energy source to the target tissue.

Page 56 16522060_1 (GHMatters) P108158.AU.1

6. The system of any one of claims 1 to5, wherein the pulsed energy source

is applied to a blood supply close to the target tissue.

7. The system of any one of claims 1 to 6, wherein the pulsed energy source

comprises laser light, microwave, radio frequency, or ultrasound.

8. The system of any one of claims 1 to 6, wherein the pulsed energy source

comprises a radio frequency between approximately three to six megahertz, a

duty cycle of between approximately 2.5% to 5%, and a pulse train duration of

between approximately 0.2 to 0.4 seconds.

9. The system of claim 8, wherein the radio frequency is generated with a

device having a coil radii of between approximately 2 and 6 mm and between

approximately 13 and 57 amp turns.

10. The system of any of claims 1 to 6, wherein the pulsed energy source

generates a microwave frequency of between approximately 10 to 20 GHz, a

pulse train duration of approximately between 0.2 and 0.6 seconds, and a duty

cycle of between approximately 2% to 5%.

11. The system of claim 10, wherein the microwave has an average power of

between approximately 8 and 52 watts.

Page 57 16522060_1 (GHMatters) P108158.AU.1

12. The system of any of claims 1 to 6, wherein the pulsed energy source

comprises a pulsed light beam having a wavelength of between approximately

530 nm to 1300 nm, a duty cycle of less than 10%, and a pulse train duration

between approximately 0.1 and 0.6 seconds.

13. The system of claim 12, wherein the pulsed light beam has a wavelength

of between 800 nm and 1000 nm and a power of between approximately 0.5

and 74 watts.

14. The system of any of claims 1 to 6, wherein the pulsed energy source

comprises pulsed ultrasound having a frequency of between approximately

1MHz and 5MHz, a train duration of between approximately 0.1 and 0.5

seconds and a duty cycle of between approximately 2% to 10%.

15. The system of claim 14, wherein the ultrasound has a power of between

approximately 0.46 and 28.6 watts.

Page 58 16522060_1 (GHMatters) P108158.AU.1