HK1237234B - Pulsating electromagnetic and ultrasound therapy for stimulating targeted heat shock proteins and facilitating protein repair - Google Patents

Description

Pulsed electromagnetic and ultrasound therapy for stimulating targeted heat shock proteins and promoting protein repair

Background Art

The present invention generally relates to activation of heat shock proteins and promotion of protein repair. More specifically, the present invention relates to systems and methods for selectively stimulating activation or production of targeted heat shock proteins and promoting protein repair using pulsed electromagnetic energy or ultrasound energy.

Heat shock proteins (HSPs) are a family of proteins produced by cells in response to exposure to stressful conditions. High levels of HSP production can be triggered by exposure to different types of environmental stressors, such as infection, inflammation, exercise, exposure of cells to toxins, starvation, low oxygen levels, or dehydration.

Heat shock proteins are known to play a role in responding to a wide range of abnormalities in body tissues, including viral infection, inflammation, malignant transformation, exposure to oxidants, toxins, and hypoxia. Several heat shock proteins act as intracellular chaperones for other proteins, and a large number of members of the HSP family are expressed or activated at low to moderate levels due to their important roles in protein maintenance and even in simply monitoring cellular proteins under non-stress conditions. These activities are part of the cell's self-repair system, known as the cellular stress response or heat shock response.

Heat shock proteins are usually named according to their molecular weight. For example, Hsp60, Hsp70 and Hsp80 refer to a family of heat shock proteins with sizes of 60, 70 and 80 kilodaltons, respectively, by order of magnitude. They work in many different ways. For example, Hsp70 has a peptide binding and ATPase domain that stabilizes protein structure in the unfolding and assembly capacity state. Mitochondrial Hsp60 forms a ring structure to promote the assembly of proteins into a natural state. Hsp90 exerts an inhibitory regulatory effect by binding to cellular tyrosine kinases, transcription factors and glucocorticoid receptors. Hsp27 inhibits protein aggregation.

Hsp70 heat shock proteins are members of the extracellular and membrane-bound heat shock proteins, and Hsp70 is involved in binding and presenting antigens to the immune system. Hsp70 has been found to inhibit the activity of influenza A virus ribonucleoprotein and block viral replication. Tumor-derived heat shock proteins can induce specific protective immunity. Experimental and clinical observations have shown that heat shock proteins are involved in the regulation of autoimmune arthritis, type 1 diabetes, measles, arteriosclerosis, multiple sclerosis, and other autoimmune reactions.

Accordingly, it is believed that it would be advantageous to be able to selectively induce a heat shock response to increase the number or activity of heat shock proteins in body tissues in response to infection or other abnormalities. However, this must be done in a controlled manner to avoid damaging or destroying the tissue or area of the body being treated. The present invention satisfies these needs and provides other related benefits.

Summary of the Invention

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

Pulsed ultrasound or electromagnetic radiation energy is applied to the target tissue to generate a thermal time course that stimulates the cells of the target tissue to activate heat shock proteins without damaging the target tissue. This involves briefly raising the temperature of the target tissue to at least 10°C, and only by 1°C or less over several minutes.

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

A device can be inserted into a cavity of the body to apply pulsed ultrasound or electromagnetic radiation energy to tissue. The device can include an endoscope.

The pulsed ultrasound or electromagnetic radiation energy can be applied to an external area of the body that is adjacent to the target tissue or has a blood supply near the surface of the external area of the body. For example, the body area can include an earlobe, and the pulsed electromagnetic radiation energy can be applied to the blood flowing through the earlobe.

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

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention is illustrated in the accompanying drawings. In these drawings:

FIG1 is a schematic diagram of a light emitting unit for generating a timing pulse train of the present invention, having a light pipe extending therefrom;

FIG2 is a cross-sectional view of a light stimulation delivery device for delivering electromagnetic energy to a target tissue according to the present invention;

FIG3 is a schematic diagram illustrating a system for generating a laser beam according to the present invention;

FIG4 is a schematic diagram of an optical device for generating a laser geometric pattern according to the present invention;

FIG5 is a schematic diagram illustrating an alternative embodiment of a system for generating a laser beam for treating tissue according to the present invention;

FIG6 is a schematic diagram illustrating another embodiment of a system for generating a laser beam for treating tissue according to the present invention;

7 is a cross-sectional schematic diagram of the end of the endoscope inserted into the nasal cavity and treating tissue in the nasal cavity of the present invention;

8 is a partial cross-sectional schematic diagram of a bronchoscope of the present invention extending through the trachea and into the bronchus of the lung and providing treatment to the lung;

FIG9 is a schematic diagram of a colonoscope of the present invention for providing light stimulation to the intestine or colon region of the body;

10 is a schematic diagram of an endoscope inserted into the stomach and providing treatment to the stomach according to the present invention;

FIG11 is a partially cutaway perspective view of a capsule endoscope used in the present invention;

FIG12 is a schematic diagram of pulsed high-intensity focused ultrasound for treating internal body tissues according to the present invention;

FIG13 is a schematic diagram of treating a patient's blood flow through the earlobe according to the present invention; and

14 is a cross-sectional view of a stimulation therapy device of the present invention for use in delivering light stimulation to the blood via the earlobe.

DETAILED DESCRIPTION

As shown in the accompanying drawings and described more fully herein, the present invention is directed to a system and method for delivering energy, such as laser, ultrasound, ultraviolet radiofrequency, microwave radiofrequency, and other similar energies, to produce a pulsed thermal time course in tissue that stimulates the activation or production of heat shock proteins and promotes protein repair without causing any damage.

The inventors of the present invention have discovered that applying electromagnetic radiation in the form of lasers of multiple wavelengths to retinal tissue without damaging or injuring the retinal tissue achieves 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 in the retinal tissue and the promotion of protein repair. This is disclosed in U.S. patent application serial number 14/607,959, filed on January 28, 2015, U.S. patent application serial number 13/798,523, filed on March 13, 2013, and U.S. patent application serial number 13/481,124, filed on May 25, 2012, the contents of which are incorporated herein by reference as if fully set forth.

The present inventors have discovered that it is possible to generate a laser beam that is therapeutic yet sublethal to cells of retinal tissue, thereby avoiding damage to the retinal tissue and providing preventative and protective photocoagulation treatment of the retinal tissue of the eye. The present inventors have discovered that generating a subthreshold, sublethal micropulse laser beam having 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, produces the desired retinal photostimulation without any visible burn area or tissue damage. More specifically, a laser beam having a wavelength between 550 nm and 1300 nm, and in a particularly preferred embodiment, 810 nm, a duty cycle of approximately 5% or less, a predetermined intensity or power (e.g., 100-590 watts per square centimeter of the retina or approximately 1 watt per laser spot at each treatment point on the retina), and a predetermined pulse length or exposure time (e.g., 50 milliseconds or less), produces sublethal, "true subthreshold" retinal photostimulation, wherein all areas of retinal pigment epithelial cells exposed to the laser irradiation are preserved in the retinal photostimulation and are available for treatment. In other words, the present inventors have discovered that elevating retinal tissue to at least therapeutic levels, but below cell- or tissue-lethal levels, replicates the benefits of the halo effect of prior art methods without destroying, burning, or otherwise damaging the retinal tissue. This is referred to herein as subthreshold diode micropulse laser therapy (SDM).

SDM does not produce laser-induced retinal damage (photocoagulation) and has no known adverse therapeutic effects, and has been reported to be effective in treating many retinopathies (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 resistance, and progressive degenerative retinal diseases such as dry age-related macular degeneration, Stargardt's disease, cone dystrophy, and retinitis pigmentosa. The safety of SDM can be achieved by using it transfoveally in eyes with a visual acuity of 20/20 to reduce the risk of vision loss due to early DME involving the fovea.

The principle of SDM's action is the production or activation of heat shock proteins (HSPs). Although there are nearly an infinite number of possible cellular abnormalities, all types of cells share a common and highly conserved repair mechanism: heat shock proteins (HSPs). HSPs can be triggered immediately, within seconds to minutes, by stress or damage to almost any type of cell. In the absence of lethal cell damage, HSPs are extremely effective in repairing and restoring living cells to a more normal state of function. Although HSPs are short-lived, generally reaching a peak within a few hours and lasting for several days, the effects of HSPs can last for a long time. HSPs reduce inflammation, a common factor in many diseases.

Laser therapy can induce the generation or activation of HSPs and alter cytokine expression. The more sudden and severe the non-lethal cellular stress (e.g., laser irradiation), the more rapid and stable the activation of HSPs. Therefore, the bursts of repetitive low-temperature thermal peaks with very large rate of change (~7°C rise per 100 μs micropulse or 70,000°C/second) generated by each SDM exposure are particularly effective in stimulating HSP activation, especially when compared to the non-lethal exposure of subthreshold treatment with continuous-wave lasers, which can only double the rise in low-mean tissue temperature.

Laser wavelengths below 550nm produce increasingly cytotoxic photochemical effects. SDM produces photothermal rather than photochemical cell stress at 810nm. Therefore, SDM is able to affect without damaging tissue. The clinical benefits of SDM are therefore primarily generated by the activation of subpathological photothermal cells, HSPs. In dysfunctional cells, the stimulation of HSPs achieved by SDM leads to standardized cytokine expression, and thereby improved structure and function. The therapeutic effect of the "low-intensity" laser/tissue interaction is then amplified by the application of "high-density" lasers, by densely/convergently treating large areas of tissue including all pathological areas to restore all dysfunctional cells in the targeted tissue area, thereby maximizing the therapeutic effect. These principles define the therapeutic strategy of SDM described herein.

Because normal functioning cells do not require repair, HSP stimulation in normal cells will tend to have no significant clinical effect. The "pathological selectivity" of near-infrared laser effects such as SDM, which affect pathological cells but not normal cells, is consistent with clinical observations of SDM across various cell types. SDM has been reported to have a broad clinical therapeutic range, unique among retinal laser modalities, and meets the "maximum permissible exposure" predictions of the American National Standards Institute. Although SDM may cause direct photothermal effects such as entropic protein unfolding and depolymerization, SDM presents an optimized clinical safety profile and effective stimulation of HSP-mediated repair.

As described above, while SDM stimulation of HSPs is nonspecific for disease processes, the results of HSP-mediated repair are achieved by their nature of targeting dysfunctional states. HSPs tend to repair errors, no matter what the error. Therefore, the effects of SDM observed in retinal conditions are very different from those seen in BRVO, DME, PDR, CSR, age-related and inherited retinal diseases, and drug-resistant NAMD. Conceptually, this device can be thought of as a "reset to default" mode of SDM action. Because cellular function is critical in a wide range of diseases, SDM normalizes cellular function by triggering a "reset" (to "factory default settings") via HSP-mediated cellular repair.

The present inventors have found that SDM treatment of patients with age-related macular degeneration (AMD) can slow down the progression or even prevent the development of AMD. Most patients have very significant improvements in intermediate visual acuity and intermediate contrast visual acuity of logarithmic visual acuity (logMAR) of dynamic function after SDM treatment. It is believed that SDM works by targeting, preserving and "normalizing" (developing towards normal) the function of retinal pigment epithelial cells (RPE).

Despite the presence of systemic diabetes, SDM has also been shown to prevent or reverse the clinical manifestations of diabetic retinopathy without treatment-related damage or adverse reactions. Based on this, it is hypothesized that SDM may work by inducing the restoration of more normal cellular function and cytokine expression in RPE cells affected by diabetes, similar to clicking the "reset" button on an electronic device to restore factory default settings. Based on the above information and research, SDM treatment may directly affect cytokine expression by targeting the activation of heat shock proteins (HSPs) in tissues.

Since heat shock proteins play a role in responding to a large number of abnormal conditions in body tissues other than ocular tissue, it is believed that similar systems and methods can be beneficially used to treat these abnormal conditions, infections, and the like. Thus, the present invention relates to the controlled application of ultrasound or electromagnetic radiation to treat inflammation, autoimmune conditions, and cancers, including those acquired through optical fibers of an endoscope or surface probe and focused electromagnetic/acoustic waves. For example, cancers on the surface of the prostate, which has the greatest risk of metastasis, can be acquired through optical fibers in a rectoscope. Colon tumors can be acquired by optical fiber systems such as those used for colonoscopy.

As described above, light stimulation with a subthreshold diode micropulse laser (SDM) effectively stimulates the direct repair of slightly misfolded proteins in ocular tissue. In addition to HSP activation, another possible mechanism is that the temperature spikes induced by the micropulses, in the form of a thermal time course, allow water to diffuse into the interior of the protein, thereby breaking the peptide-peptide hydrogen bonds that prevent the protein from returning to its native state. Water diffusion into the protein increases the number of inhibited hydrogen bonds by an order of magnitude of nearly 1,000. Therefore, it is believed that this process may also be beneficially applied to other diseases.

Light stimulation according to the present invention can be effectively delivered to the inner surface area or tissue of the body using an endoscope, such as a bronchoscope, proctoscope, colonoscope or the like. Each endoscope basically consists of a flexible tube that itself contains one or more inner tubes. Typically, one of the inner tubes includes a light tube or multimode optical fiber that transmits light to the endoscope to illuminate the target area and enable the doctor to see what is on the illuminated end. Another inner tube can be composed of a wire carrying an electric current so that the doctor can burn the irradiated tissue. Another inner tube can be composed of a biopsy tool that allows the doctor to cut and grasp any irradiated tissue.

In the present invention, one of the inner tubes serves as an electromagnetic radiation tube, such as a multimode optical fiber, to ultimately deliver SDM or other electromagnetic radiation pulses into a scope held by a physician. Referring now to FIG1 , a light emitting 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 and pulsed manner. The electromagnetic radiation is then delivered to the distal end of a scope 14 via a light pipe or tube 12. As shown in FIG2 , the scope 14 is inserted into the body and the laser light or other radiation 16 is delivered to the target tissue 18 to be treated.

Referring now to FIG3 , a schematic diagram of a system for generating electromagnetic energy radiation, such as a laser, including an SDM, is shown. The system, generally designated 20 , includes a laser control console 22 , such as, in the preferred embodiment, an 810 nm near-infrared micropulse diode laser. The laser generates a laser beam, which, as desired, passes through optics such as an optical lens or mask, or through a plurality of optical lenses and/or masks 24 . Laser projection optics 24 deliver the shaped beam to a delivery device 26 , such as an endoscope, for projecting the laser beam onto target tissue in a patient. It should be understood that the box designated 26 may represent both a laser beam projector or delivery device and a monitoring system/camera, such as an endoscope, or may comprise both distinct components in use. The monitoring system/camera 26 provides feedback to a display monitor 28 , which may also include the necessary computer hardware, data input, and controls for operating the laser 22 , the optics 24 , and/or the projection/monitoring component 26 .

Referring now to FIG4 , in one embodiment, a laser beam 30 may pass 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 that simultaneously produces multiple laser spots or other geometric objects. This is represented by multiple laser beams labeled 36. Alternatively, the multiple laser spots may be produced by multiple fiber optic waveguides. Any method of producing laser spots enables the simultaneous production of a very large number of laser spots over a very wide treatment field of view. In fact, a very large number, potentially up to hundreds or even thousands or more, of laser spots may be produced simultaneously to cover a specified area of the target tissue, or possibly even the entire target tissue. A series of applications of small, separate laser spots applied simultaneously may be appropriate to avoid certain disadvantages and treatment risks known to be associated with the application of large laser spots.

Utilizing optical features with characteristic dimensions comparable to the wavelength of the applied laser light, such as diffraction gratings, makes it possible to exploit quantum mechanical effects that allow a large number of laser spots to be simultaneously applied to very large target areas. Each spot generated by these diffraction gratings has an optical geometry similar to that of the input beam, and the power variation of each spot is minimized. The result is multiple laser spots with sufficient irradiance to simultaneously deliver harmless and effective therapeutic applications over large target areas. The present invention also contemplates the use of other geometric objects and patterns generated by other diffractive optical elements.

The laser light diffracts through mask 34 and produces a periodic pattern at some distance from mask 34, as shown by the laser beam labeled 36 in FIG4 . A single laser beam 30 thus forms hundreds or even thousands of individual laser beams 36 to produce the desired pattern of light spots or other geometric objects. These laser beams 36 may pass through additional lenses 38, collimators 40, etc. to direct the laser beams and form the desired pattern. These additional lenses 38, collimators 40, etc. may further transform and redirect the laser beams 36 as needed.

Any arbitrary pattern can be constructed by controlling the shape, spacing, and pattern of optical mask 34. The pattern and exposure spot can be freely created and modified by experts in the field of optical engineering according to the needs of the application. Photolithography techniques, particularly those developed in the field of semiconductor manufacturing, can be used to create simultaneous geometric patterns of light spots or other objects.

FIG5 illustrates a system for coupling multiple light sources into the pattern generating optical subassembly described above. Specifically, the system 20′ is similar to the system 20 described above in FIG3 . The primary difference between the alternative system 20′ and the earlier described system 20 is the inclusion of multiple laser consoles, the outputs of which are each fed into a fiber optic coupler 42. As described in the earlier system, the fiber optic coupler produces a single output that is transmitted to the laser projector optics 24. The fiber optic coupler 42 is used to achieve the coupling of multiple laser consoles 22 into a single optical fiber, as is known in the art. Other known mechanisms for combining multiple light sources are possible and may be used in place of the fiber optic coupler described herein.

In this system 20', multiple light sources 22 follow a similar path as described in the earlier system 20, such as collimation, diffraction, realignment, and guidance to the projector device and/or tissue. In this alternative system 20', the diffraction element must operate in a different path than previously described, depending on the wavelength of the light passing through it, resulting in slight variations in the pattern. These variations are linearly related to the wavelength of the light being diffracted. Generally, the differences in diffraction angles are small enough that different, overlapping patterns can be guided along the same optical path through the projection device 26 to the tissue for treatment.

Since the resulting pattern will vary slightly for each wavelength, the continuous offset to achieve complete coverage will be different for each wavelength. This continuous offset can be accomplished in two modes. In the first mode, all wavelengths of light are applied simultaneously without having identical coverage. An offset steering pattern is used to achieve complete coverage of one of the multiple wavelengths. Therefore, when the selected wavelength of light achieves complete coverage of the tissue, the application of the other wavelengths achieves incomplete or overlapping coverage of the tissue. The second mode continues to apply varying wavelengths in an appropriate steering pattern for that particular wavelength to achieve complete coverage of the tissue. This mode eliminates the possibility of using multiple wavelengths for treatment simultaneously, but allows the optical method to achieve identical coverage for each wavelength. This avoids incomplete or overlapping coverage of any wavelength of light.

These modes can also be mixed and matched. For example, two wavelengths can be applied simultaneously, with one wavelength providing complete coverage and the other providing incomplete or overlapping coverage, followed by a third wavelength applied sequentially for complete coverage.

Figure 6 illustrates yet another alternative embodiment of the innovative system 20". The system 20" is generally configured identically to the system 20 shown in Figure 3. The primary difference is the inclusion of multiple pattern generating subassembly channels tuned to specific wavelengths of the light source. Multiple laser consoles 22 are arranged parallel to one another, and each laser console feeds directly into its own laser projector optics 24. The laser projection optics for each channel 44a, 44b, 44c include a collimator 32, a mask or diffraction grating 34, and realigners 38, 40, as described above in connection with Figure 4 - the entire set of optics being tuned to the specific wavelength produced by the corresponding laser console 22. The output of each set of optics 24 is then directed to a beam splitter 46 which is combined with other wavelengths. It is known to those skilled in the art that a beam splitter used in reverse can be used to combine multiple beams into a single output.

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

In this system 20", the optical elements of each channel are tuned to produce a specifically specified pattern for the wavelength of that channel. Therefore, when all channels are combined and properly aligned, a single steering pattern can be used to achieve complete coverage of the tissue for all wavelengths.

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 used in the treatment.

Implementations of system 20" can exploit various symmetries to reduce the number of alignment constraints. For example, the proposed grid pattern is periodic in two dimensions and steers in two dimensions to achieve complete coverage. As a result, if the pattern for each channel is the same as specified, the actual pattern for each channel does not need to be aligned to the same steering pattern to achieve complete coverage of all wavelengths. Each channel will only require optical alignment for effective combining.

In system 20", each channel begins with a light source 22, which can be from an optical fiber, as in other embodiments of the pattern generating subassembly. The light source 22 is directed to an optical assembly 24 for collimation, diffraction, realignment, and to a beam splitter where the channel is combined with the main output.

It should be understood that the laser generating system shown in Figures 3-6 is exemplary. Other devices and systems can be used to generate the light source of the SDM laser, and the light source of the SDM laser is typically in the form of an endoscope with a light pipe or a light pipe-like object, which is practicable through to the projector device. Other forms of electromagnetic radiation can also be generated and used, including ultraviolet waves of predetermined wavelengths, microwaves, other radio frequency waves and lasers. In addition, ultrasound can also be generated and used to generate sufficient thermal time course temperature peaks in the target tissue to activate or generate heat shock proteins in the cells of the target tissue without damaging the target tissue itself. To achieve this, typically, an ultrasound source or an electromagnetic radiation energy source is provided and applied to the target tissue in the form of instantaneous increase in the temperature of the target tissue, for example, to at least 10°C, and only 1°C or less for a long period of time, for example, for several minutes, such as 2 minutes or more.

For deep tissues that are not close to internal orifices, light pipes are not an effective method of delivering pulsed energy. In such cases, pulsed low frequency electromagnetic energy or preferably pulsed ultrasound can be used to induce a series of temperature peaks in the target tissue.

Therefore, according to the present invention, a pulsed ultrasound source or electromagnetic radiation source is applied to the target tissue to stimulate the production or activation of HSPs and promote protein repair in living animal tissue. Generally, the electromagnetic radiation can be ultraviolet waves, microwaves, other radiofrequency waves, lasers, etc. of a predetermined wavelength. On the other hand, if the electromagnetic energy is applied to a deep tissue target away from natural orifices, the absorption length is limited to the wavelength of the microwave or radiofrequency wave based on the depth of the target tissue. However, as explained later, for ultrasound waves applied to deep tissue targets away from natural orifices, long-wavelength electromagnetic radiation is preferred.

The ultrasound or electromagnetic radiation is pulsed to produce a thermal time course in the tissue that stimulates the production or activation of HSPs and promotes 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 to keep the temperature peak on the order of a few degrees, for example, about 10°C, while maintaining a long-term temperature increase of less than the 1°C limit specified by the FDA. It is known that if too large an area or volume of tissue is treated, the elevated temperature of the tissue cannot spread rapidly enough to meet FDA requirements. However, limiting the area and/or volume of the tissue being treated and the energy source for generating the pulses enables the present invention to stimulate the activation or production of HSPs by heating or otherwise stressing cells and tissues, while allowing the treated cells and tissues to dissipate any excess heat generated within acceptable limits.

It is believed that the stimulation of HSP production according to the present invention can be effectively utilized in treating a variety of tissue abnormalities, disorders, and even infections. For example, viruses that cause colds primarily affect the small openings of the respiratory epithelium in the nasal passages and nasopharynx. Similar to the retina, the respiratory epithelium is a thin, clear tissue. Referring to FIG7 , a cross-sectional view of a human head 48 is shown, wherein an endoscope 14 is inserted into a nasal cavity 50 and energy 16, such as a laser or laser-like, is directed to tissue 18 to be treated within the nasal cavity 50. The tissue 18 to be treated can be within the nasal cavity 50, including the nasal cavity and nasopharynx.

To ensure absorption of the laser energy or other energy source, the wavelength can be adjusted to the infrared (IR) absorption peak of water or an auxiliary dye used as a photosensitizer can be used. In this case, the subsequent treatment will include drinking or topically applying an adjuvant, waiting a few minutes for the adjuvant to penetrate the surface tissue, and then applying the laser or other energy source 16 to the target tissue 18 for a few seconds, for example, through an endoscope 14 as shown in Figure 7. To improve patient comfort, the endoscope 14 can be inserted after the administration of a local anesthetic. If necessary, this procedure can be repeated regularly, for example, once a day or so.

As discussed above, treatment will stimulate the activation or production of heat shock proteins and promote protein repair without damaging the cells and tissues to be treated. As discussed above, it has been found that certain heat shock proteins play an important role in immune responses and the health of target cells and tissues. The energy source can be, for example, a monochromatic laser with a wavelength of 810 nm, which is applied in a manner similar to that described in the aforementioned patent application, but is applied through an endoscope or the like as shown in Figure 7. The selection of auxiliary dyes is to increase the absorption of the laser. Although this includes specific preferred methods and embodiments for implementing the present invention, it should be understood that according to the present invention, other types of energy and delivery devices can be used to achieve the same purpose.

Referring now to Figure 8, a similar situation exists for influenza virus, where the primary target is the epithelium of the upper respiratory tree, portions greater than approximately 3.3 mm in diameter, i.e., the upper six generations of the upper respiratory tree. A thin layer of mucus separates the target epithelial cells from the tracheal lumen, and it is within this mucus layer that antigen-antibody interactions occur, leading to viral inactivation.

Continuing with FIG8 , the flexible light tube 12 of the bronchoscope 14 is passed through the patient's mouth 52, through the throat and trachea 54, and into a bronchus 56 of the respiratory tree. Laser or other energy source 16 is applied and delivered to the tissue in this uppermost region, treating the tissue and region in the same manner as described above with reference to FIG7 . It is contemplated that the wavelength of the laser or other energy source can be selected to match the IR absorption peak of water trapped in the mucus, thereby heating the tissue and stimulating the activation or production of HSPs and promoting protein repair, with attendant additional benefits.

9 , a colonoscope 14 can be used to insert a flexible optical tube 12 therein through the anus and rectum 58 and into the large intestine 60 or small intestine 62 to deliver a selected laser or other energy source 16 to the area and tissue to be treated, as shown. This can be used to assist in the treatment of colon cancer and other gastrointestinal problems.

Typically, the procedure can be performed similar to a colonoscopy, in which the bowels are cleared of any feces, the patient lies on their side, and the physician inserts the elongated, light-tube portion 12 of the colonoscope 14 into the rectum and moves the elongated, light-tube portion 12 of the colonoscope 14 into the region of the colon, large intestine 60, or small intestine 64 to the region to be treated. The physician can monitor the path of the inserted flexible member 12 on a monitor and even observe the tissue at the tip of the colonoscope 14 within the intestine in order to observe the region to be treated. Using one of the other optical fibers or light tubes, the tip 64 of the scope is guided to the tissue to be treated, and a laser source or other source of radiation 16 is delivered through one of the light tubes of the colonoscope 14 to treat the region of tissue to be treated, as described above, to stimulate the activation or production of HSPs in the tissue 18.

Referring now to FIG10 , another example in which the present invention may be advantageously used is a condition of the gastrointestinal (GI) tract often referred to as "leaky gut" syndrome, a condition characterized by inflammation and other metabolic dysfunction. Since the GI tract is susceptible to metabolic dysfunction similar to that of the retina, it is expected to respond well to treatment according to the present invention. This may be accomplished by subthreshold, diode micropulse laser (SDM) therapy as described above, or other energy sources and devices discussed herein and known in the art.

10 , a flexible light tube 12 of an endoscope or the like is passed through the patient's mouth 52, through the throat and trachea area 54, and into the stomach 66, with its tip or end 64 directed toward the tissue 18 to be treated and a laser or other energy source 16 directed toward the tissue 18. It will be understood by those skilled in the art that a colonoscope may also be used and inserted through the rectum 58 and into the stomach 66 or any tissue between the stomach and the rectum.

If desired, chromophore pigments can be delivered orally to GI tissues to achieve absorption of the radiation. For example, if unfocused 810 nm radiation from a laser diode or LED is used, the pigment has an absorption peak at or near 810 nm. Alternatively, the wavelength of the energy source can be adjusted to a slightly longer wavelength at the water absorption peak, thus eliminating the need for externally applied chromophores.

The present invention contemplates that a capsule endoscope 68, such as that shown in FIG. 11 , can be used to administer radiation and energy sources according to the present invention. Such capsules are relatively small, for example, approximately one inch in length, to facilitate swallowing by the patient. As the capsule or pill 68 is swallowed and passed through the gastrointestinal tract, once properly positioned, the capsule or pill 68 can receive power and signals, such as via antenna 70, to activate an energy source 72, such as a laser diode and associated circuitry. This energy source, through a suitable lens 74, focuses the generated laser light or radiation through a non-radioactive cover 76 and onto the tissue to be treated. It should be understood that the position of the capsule endoscope 68 can be determined by various methods, such as external imaging, signal tracking, or even by a miniature camera with a light that allows the physician to view images of the capsule or pill 68 as it passes through the gastrointestinal tract. The capsule or pill 68 can be powered by its own power source, such as a battery or externally via an antenna, to enable the laser diode 72 or other energy generator to generate energy of the desired wavelength and pulses to treat the tissue or area to be treated.

As with the retina treatment in the previous application, the radiation will be pulsed to take advantage of the micropulse temperature peaks and associated safety features, and the power can be adjusted to make the treatment completely harmless to the tissue. This may involve adjusting the peak power, pulse time, and repetition rate to keep the peak temperature rise around 10°C while keeping the long-term temperature rise below the FDA limit of 1°C. If a pill form of delivery 68 is used, the device can be powered by a small rechargeable battery or by wireless inductive stimulation or the like. The heated/stressed tissue will stimulate the activation or production of HSPs and promote protein repair with its attendant benefits.

From the foregoing examples, the technology of the present invention is limited to the treatment of conditions near the body surface or internal surfaces that are easily reached by optical fiber or other optical delivery devices. The reason why the application of SDM in activating HSPs is limited to areas near the body surface or optically accessible is that the absorption length of IR or visible radiation in the body is very short. However, conditions deeper in the cell or human body can benefit from the present invention. Therefore, the present invention contemplates the use of ultrasound and/or radio frequency (RF) or even electromagnetic (EM) radiation of shorter wavelengths in body tissues, and which has a relatively long absorption length. As described more fully below, the use of pulsed ultrasound is superior to RF electromagnetic radiation to activate remedial HSPs in abnormal tissues that cannot be reached by surface SDMs or the like. Pulsed ultrasound sources can also be used for abnormalities at or near the surface.

12, using ultrasound, specific areas deep within the body can be targeted by one or more beams each focused onto the target site. The pulsed heating will then be primarily only in the target area where the beams are focused and overlap.

As shown in FIG12 , an ultrasonic transducer 78 or the like generates a plurality of ultrasonic beams 80 coupled to the skin via an acoustic impedance matching gel. The ultrasonic beams 80 pass through the skin 82 and through intact tissue in front of the focus of the beams 80 to reach a target organ 84, such as the liver, as shown, and more specifically, to the target tissue 86 to be treated where the ultrasonic beams 80 are focused. As described above, pulse heating will occur only at the target focal region 86 where the focused beams 80 overlap. Tissue in front of and behind the focal region 86 will not be significantly heated or affected.

Examples of parameters that produce a desired HSP activation Arrhenius integral greater than 1 and a damage Arrhenius integral less than 1 are a total ultrasound power between 5.8 and 17 watts, a pulse duration of 0.5 seconds, an interval between pulses of 5 seconds, and a total number of pulses of 10 within a total pulse flow time of 50 seconds. The target treatment volume is approximately 1 mm on a side. Larger treatment volumes can be achieved by applying multiple ultrasound waves applied simultaneously to adjacent but spaced and aligned columns using an ultrasound system similar to the laser diffraction optical system (described in paragraph 45). As described above, multiple focused ultrasound beams converge on a very small treatment target in the body, and the convergence achieves minimal heating of the beams except for overlap at the target. This area will be heated and stimulate the activation of HSPs and promote protein repair through a brief high temperature peak. However, given the pulsed aspect of the invention and the relatively small area to be treated at any given time, the treatment meets the FDA/FCC requirement of a long-term (minutes) average temperature rise of <1K. An important difference between the present invention and existing clinical heating treatments for pain and muscle strain is that the existing technology does not have a high T peak, which is required to effectively activate HSPs and promote protein repair to provide healing at the cellular level.

As far as activation of remedial HSPs and protein repair is concerned, the pulse train mode of energy delivery has a clear advantage over single pulse or gradual energy delivery. There are two considerations that constitute this advantage:

First, a major advantage of HSP activation and protein repair in the SDM energy transfer model comes from the resulting peak temperature of approximately 10°C. This large temperature rise has a significant impact on the Arrhenius integral, which quantifies the number of activated HSPs and the rate of water diffusion into the protein, which promotes protein repair. This is because temperature constitutes an exponential with amplifying effects.

It is important that the temperature rise not remain high (10+ degrees) for an extended period of time, as this would violate FDA and FCC requirements that the average temperature rise must be less than 1°C over a period of several minutes.

The SDM mode of energy delivery uniquely meets the above considerations through judicious selection of power, pulse time, pulse interval, and the volume of the target area to be treated. The volume of the treatment area is a consideration because the temperature must decay fairly quickly from its high value of approximately 10°C so that the long-term average temperature rise does not exceed the long-term FDA/FCC limit of 1°C.

For an area of linear dimension L, the time it takes for the peak temperature to e-fold in tissue is approximately ^L² /16D, where D = 0.00143 ^cm² /second is a typical thermal diffusivity. For example, if L = 1 mm, the decay time is approximately 0.4 seconds. Therefore, for an area of 1 mm on a side, a series of 10 pulses, each with a duration of 0.5 seconds and a 5-second pulse interval, can achieve the desired transient temperature rise while still not exceeding a 1°C increase in the average long-term temperature. This is further demonstrated below.

The limitation of the heated volume is because RF electromagnetic radiation is not a good choice for SDM-type treatment of deep areas of the body. The long skin depth (penetration distance) and resistive heating along the skin depth result in a large heated volume. The thermal inertia of the heated volume does not allow for reaching a high peak temperature to activate HSPs and promote protein repair, nor does it allow for a rapid temperature decay that meets long-term FDA and FCC limits on average temperature rise.

Ultrasound has been used to therapeutically heat areas of the body to relieve pain and muscle strain. However, the heating did not follow an SDM-type protocol and did not result in a temperature spike that stimulates HSP.

Next, consider a focused ultrasound beam directed to a target area deep within the body. To simplify the math, assume the beam is replaced by a single spherical source focused at the center of the sphere. The absorption length of ultrasound can be quite long. Table 1 below shows typical absorption coefficients for 1 MHz ultrasound. The absorption coefficient is roughly proportional to the frequency.

Table 1. Typical absorption coefficients of 1 MHz ultrasound in body tissues:

Attenuation coefficient of body tissue at 1MHz (cm ^-1 )

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

I(r)＝P/(4πr ² ) [1]

Where P represents the total ultrasonic power.

Then the temperature rise at the distance r and at the end of the short pulse duration _tp is

dT(t _p )=Pαt _p /(4πC _v r ² ) [2]

Where α is the absorption coefficient and Cv is the specific heat capacity at constant volume. This formula is only valid when r reaches a distance where the thermal diffusion length of _tp is almost the same as r, or when the focused beam reaches the diffraction limit. For small r, the temperature rise is essentially independent of r. As an example, assume that the diffraction limit is reached at a distance smaller than the radiation distance determined by thermal diffusion. Then

r _dif =(4Dt _p ) ^1/2 [3]

where D is the thermal diffusivity and for r < r _dif , the temperature rise at t _p is

dT(r _dif ,t _p )=3Pα/(8πC _v D) when r<r _dif [4]

Therefore, at the end of the pulse we can write the increase in temperature:

dT _p (r)＝{Pαt _p /(4πC _v }[(6/r _dif ² )U{r _dif -r)+(1/r ² )U(rr _dif )] [5]

For the heat diffusion equation, Green’s function is used.

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

When applied to the initial temperature distribution, we find that the temperature dT(t) of the focus r = 0 at time t is

dT(t)＝[dT _o /{(1/2)+(π ^1/2 /6)}][(1/2)(t _p /t) ^3/2 +(π ^1/2 /6)(t _p /t)] [7]

and

dT _o ＝3Pα/(8πC _v D) [8]

A good approximation to equation [7] is provided by the following formula:

dT(t)≈dT _o (t _p /t) ^3/2 [9]

This is shown in the graph 1 below.

Figure 1. Comparison of equations [7] and [9] for dT(t)/dT _o in the target treatment area. The bottom curve is an approximate expression for equation [9]. The Arrhenius integral for the N pulse sequence can now be evaluated using the temperature rise obtained from equation [9]. In this expression,

dT _N (t)＝∑dT(t-nt _I ) [11]

where dT(t-nt _I ) is the expression of equation [9] with t-nt _I replacing t and t _I designates the interval between pulses.

The Arrhenius integral can be approximately evaluated by dividing the integration interval into a portion where the temperature peak occurs and a portion where the temperature peak does not occur. The sum of the contributions from the temperature peaks can be simplified by applying Laplace's end point formula to the integral over the temperature peaks. Furthermore, the integral over the portion where the peaks do not occur can be simplified by noting that the non-peak temperature rises reach the asymptotic value very quickly, thus obtaining a good approximation by substituting the asymptotic value for the varying time rise. When these approximations are obtained, equation [10] becomes:

Ω＝AN[{t _p (2k _B T _o ² /(3EdT _o )}exp[-(E/k _B )1/(T _o +dT _o +dT _N (Nt _I ))]

+exp[-(E/k _B )1/(T _o +dT _N (Nt _I ))]] [12]

in

dT _N (Nt _I )≈2.5dT _o (t _p /t _I ) ^3/2 [13]

(The 2.5 in equation [13] comes from the sum of n over (Nn) ^-3/2 , and is of the order of (N,3/2) for typical harmonic numbers of N involved).

It is very interesting to compare this expression with that for SDM applied to the retina. The first period is very similar to the period of the peak contribution in the retinal case, except that the effective peak interval is reduced by a factor of 3 in the case of a 3D convergent beam. The second period involving _dTN ( _NtI ) is much smaller than that in the retinal case. The rise in background temperature is comparable to the rise in peak temperature. However, in the case of a convergent beam, the rate of rise in background temperature ( _tp / _tI ) ^3/2 is smaller. This points to the importance of the peak contribution to the activation or production of HSPs and the promotion of protein repair, since the rise in background temperature is similar to that in the case of continuous ultrasound heating and is negligible compared to the peak contribution. At the end of the pulse sequence, even this low background temperature rise quickly disappears due to thermal diffusion.

The lower graph 2 shows the magnitude of the logarithm of the Arrhenius integral for damage and for HSP activation or generation as a function of dTo for a pulse duration _tp = 0.5 sec, an interval between pulses _ti = 10 sec, and a total number of pulses N = 10.

Figure 2. Logarithm of the Arrhenius integral for damage and for HSP activation [Equation 12] as a function of temperature rise in degrees Kelvin from a single pulse dT _o , for pulse duration t _p = 0.5 seconds, pulse interval t _I = 10 seconds, and total number of ultrasound pulses N = 10. Figure 2a shows the logarithm of the damage integral in terms of Arrhenius constants A = 8.71 x 10 ³³ sec ^-1 and E = 3.55 x ^{10 -12} erg. Figure 2b shows the logarithm of the HSP activation integral in terms of Arrhenius constants A = 1.24 x 10 ²⁷ sec ^-1 and E = 2.66 x ^{10 -12} erg. The graphs show the conditions required to repair cells without damaging them, with Ω _damage not exceeding 1 until dT _o exceeds 11.3 K, while Ω _HSP is greater than 1 throughout the interval shown.

Equation [8] shows that when α = 0.1 cm ^-1 , a dT _o of 11.5 k can be achieved with a total ultrasonic power of 5.8 watts. This is easily achievable. If α is increased by a factor of 2 or 3, the resulting power remains readily achievable. The volume of the region where the temperature rises is a constant 0.00064 cc (e.g., corresponding to r = r _d = (4Dt _p ) ^1/2 volume). This corresponds to a cube with a side of 0.86 mm.

This simple example demonstrates that focused ultrasound can be used to stimulate the depth of repaired HSPs using readily available equipment:

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

The present invention contemplates not only the treatment of surface or near-surface tissues, such as with lasers or the like, and the treatment of deep tissues, such as with focused ultrasound beams or the like, but also the treatment of blood disorders, such as sepsis. As noted above, focused ultrasound beams can be used on both surface and deep body tissues and can also be applied to blood treatments. However, SDM and similar treatment options, which are typically limited to surface or near-surface treatment of epithelial cells and the like, are also contemplated for use in areas accessible through relatively thin layers of tissue, such as the earlobe, to treat blood disorders.

13 and 14 , treatment of blood disorders simply requires transmitting SDM or other electromagnetic radiation or ultrasound pulses to the earlobe 88, where the SDM or other radiation energy source can pass through the earlobe tissue and enter the blood flowing through the earlobe. It should be understood that this method can be performed in other areas of the human body where blood flow is relatively high and/or close to the tissue surface, such as the fingertips, the inside of the mouth or throat, etc.

13 and 14 , the earlobe 88 is shown adjacent a clamping device 90 configured to deliver SDM radiation or the like. This can be, for example, via one or more laser diodes 92 that can deliver the desired pulses and pulse trains at the desired frequency to the earlobe 88. The power can be provided by, for example, a lamp driver 94. Alternatively, the lamp driver 94 can be the actual source of the laser light, which will be delivered to the earlobe 88 via appropriate optics and electronics. The clamping device 90 will simply serve to clamp the patient's earlobe and confine the radiation to the patient's earlobe 88. This can be achieved by mirrors, reflectors, diffusers, etc. This can be controlled by a control computer 96, which will be operated by a keyboard 98 or the like. If desired, the system can also include a display and speaker 100, for example, if the procedure is performed by an operator at some distance from the patient.

The proposed treatment using a series of electromagnetic or ultrasound pulses has two major advantages over earlier treatments that involved delayed brief or sustained (long) pulses. First, the short (preferably sub-second) individual pulses in the series activate cellular reset mechanisms, such as the activation of HSPs that have reaction rate constants that are larger than those operating on longer (minutes or hours) time scales. Second, the repetitive pulses in the treatment provide a large thermal peak (on the order of 10,000), and this thermal peak allows the cellular repair system to more quickly overcome the activation energy barrier that separates the dysfunctional cellular state from the desired functional state. The end result in this sense is a "lower therapeutic threshold," i.e., lower applied average power and total applied energy can be used to achieve the desired therapeutic goal.

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 thereto, except as in the appended claims.

Claims (14)

1. A system for controllably stimulating the activation of heat shock proteins in tissues, characterized by: The source of the pulsed laser has predetermined energy parameters including a wavelength between 530 nm and 1300 nm, power, pulse length of 500 ms or less, and duty cycle of less than 10%, which instantaneously raise the temperature of the target tissue by 10 degrees Celsius at least during the application of the pulsed laser to the target tissue, and raise it by only or less than 1 degree Celsius over several minutes to generate a thermal time process in order to stimulate the cells of the target tissue to activate heat shock proteins without damaging the target tissue. 2. The system of claim 1, wherein multiple laser beams are simultaneously applied to the target tissue. 3. The system of claim 1, further comprising an insertable device into a body cavity for applying pulsed laser light to target tissue. 4. The system of claim 3, wherein the device comprises an endoscope. 5. A system suitable for controllable activation of heat shock proteins in tissues, comprising: A laser control console used to generate a laser beam. Laser projection optics Projector device, and Display monitor, characterized by: The laser beam has a wavelength between 530 nm and 1300 nm, a duty cycle of less than 10%, and a pulse length of 500 milliseconds or less to generate a thermal time process to briefly raise the temperature of the target tissue by at least 10 degrees Celsius, or by only 1 degree Celsius or less over several minutes, without damaging the target tissue. 6. The system of claim 5, wherein multiple laser beams are simultaneously applied to the target tissue. 7. The system of claim 5, further comprising an insertable device within a body cavity for applying a laser beam to target tissue, wherein the insertable device within the body cavity comprises an endoscope. 8. A system for controllably stimulating the activation of heat shock proteins in tissues, characterized by: a pulsed ultrasound source having predetermined energy parameters including wavelength or frequency, power, total pulse sequence duration and duty cycle, which, at least during the application of pulsed ultrasound to the target tissue, causes the temperature of the target tissue to momentarily rise by about 10 degrees Celsius, and rises by only or less than 1 degree Celsius over several minutes to generate a thermal time course, so as to stimulate the cells of the target tissue to activate heat shock proteins without damaging the target tissue; The ultrasound has a power of 5.8-17 watts, a pulse duration of 0.5 seconds, a pulse interval of 5 seconds, and a total pulse sequence duration of 50 seconds, with a total number of pulses of 10. 9. A system suitable for controllably stimulating the activation of heat shock proteins in tissues, comprising: Multiple laser control consoles used to generate laser beams, Optical components of laser projectors Fiber optic coupler Projector device, and Display monitor, characterized by: The laser beam has a wavelength between 530nm and 1300nm, a duty cycle of less than 10%, and a pulse length of 500 milliseconds or less to generate a thermal time progression, thereby instantly raising the temperature of the target tissue by at least 10 degrees Celsius, while raising it by only or less than 1 degree Celsius over several minutes without damaging the target tissue. 10. The system of claim 9, wherein multiple laser beams are simultaneously applied to the target tissue. 11. The system of claim 9, further comprising an apparatus insertable into a cavity of a human body to apply a laser beam to target tissue, wherein the apparatus comprises an endoscope. 12. A system suitable for controllably stimulating the activation of heat shock proteins in tissues, comprising: Multiple laser control consoles used to generate laser beams, The laser projector optics associated with the laser control console, Laser beam splitter, Projector device, and Display monitor, characterized by: The laser beam has a wavelength between 530nm and 1300nm, a duty cycle of less than 10%, and a pulse length of 500 milliseconds or less to generate a thermal time progression, thereby instantly raising the temperature of the target tissue by at least 10 degrees Celsius, while raising it by only or less than 1 degree Celsius over several minutes without damaging the target tissue. 13. The system of claim 12, wherein multiple laser beams are simultaneously applied to the target tissue. 14. The system of claim 12, further comprising an apparatus insertable into a cavity of a human body to apply a laser beam to target tissue, wherein the apparatus comprises an endoscope.