Non-Invasive Convergent Heating Treatment

Abstract

The invention relates to medical therapy of detrimental lesions. A system treats with non-invasive arrays of non-ionizing energy-radiation sources. The external sources focus energy dose distribution to a selected volume in a body. Energy output is directed towards a pathologic location and quenched around other sites or healthy tissue. Beam aiming is done without source movement. Targeted, volumetrically discrete energy deposition can beneficially manipulate lesions within the body. The purpose of the focused and enhanced energy deposition is to repair or disable pathologic physiology or structures, nerve pathways, extracellular fluid, and misfolded proteins. Locally augmented energy is used to enhance immunity, release pharmaceutical compounds from energy-sensitive vesicles and reconfigure or eliminate misfolded proteins and their aggregates. Targeted tissue may have enhanced sensitivity to received energy via a non-ionizing-radiation, treatment-localizing agent. This system optimizes delivery of non-ionizing, non-ablating electromagnetic or mechanical energy, degrading or repairing an abnormality upon interaction with it.

Claims

1. A system comprising: a. a distribution of energy radiating sources, which are external and around a body, or head and central nervous system, to treat and image pathologic lesions; b. wherein the radiated energy is non-ionizing, non-ablating electromagnetic or mechanical; c. wherein the radiated energy comprises a combination of non-ionizing output or beams selected from the group consisting of microwave radiation, radiofrequency radiation, long radio waves, laser emissions, visible, ultraviolet and solar light, infrared and far infrared light, thermal chambers, or incubators, diathermy or high-frequency electric currents, pulsed, mechanical or acoustic waves, ultrasound and high-intensity focused ultrasound (HIFU), heat from nano-devices and warm water; d. wherein the energy is delivered non-invasively without employing a device or mechanism to cut, puncture or traumatically penetrate skin or other surface, and without an open surgical procedure; e. wherein the energy-emitting sources are aligned in a localized, or circumferential, or ring or spherical distribution around a patient, as a stand-alone arrangement, or moved by a robot or gantry, or in a surface conforming and adhering layout, as a wearable; f. a phased array of the non-ionizing energy sources, electronically or computer controlled, to shift and contour their output or beams in different directions without moving the sources, for discrete and localized delivery of energy dose to a given depth or lateral position in the body with a narrow or focused distribution; g. wherein the resulting contoured energy output or beams are concentric, converging electromagnetic energy beams and deposit energy dose in a localized volume of interest to treat pathologic tissue; h. wherein the conforming volume is discrete, encompassing and customized to a detrimental phase or lesion within the body, thereby enhancing restoration of control parameters to a normal physiologic range and thus enabling a healthy transition state; i. electronic or computerized controls for source and system operation with a connected power supply with cooling; j. imaging for planning and guidance, a computer with treatment planning software, which can upload images for planning and guidance, and is connected to an information system with record and verify software; k. a medium storing computer-executable process steps to reconstruct medical images and calculate therapeutic effects of the localized non-ionizing radiation of energy treatment; l. a treatment table or chair capable of movement in three dimensions; m. a non-ionizing-radiation, treatment-localizing agent to treat diseased tissue in response to received radiation of energy; and n. non-invasive or invasive thermometry.

2. A device comprising: a. a distribution of energy radiating sources, which are external and around a body, or head and central nervous system, to treat and image pathologic lesions; b. wherein the radiated energy is non-ionizing, non-ablating electromagnetic or mechanical; c. wherein the radiated energy comprises a combination of non-ionizing output or beams selected from the group consisting of microwave radiation, radiofrequency radiation, long radio waves, laser emissions, visible, ultraviolet and solar light, infrared and far infrared light, thermal chambers, or incubators, diathermy or high-frequency electric currents, pulsed, mechanical or acoustic waves, ultrasound and high-intensity focused ultrasound (HIFU), heat from nano-devices and warm water; d. wherein the energy is delivered non-invasively without employing a device or mechanism to cut, puncture or traumatically penetrate skin or other surface, and without an open surgical procedure; e. wherein the energy-emitting sources are aligned in a localized, or circumferential, or ring or spherical distribution around a patient, as a stand-alone arrangement, or moved by a robot or gantry, or in a surface conforming and adhering layout, as a wearable; f. a phased array of the non-ionizing energy sources, electronically or computer controlled, to shift and contour their output or beams in different directions without moving the sources, for discrete and localized delivery of energy dose to a given depth or lateral position in the body with a narrow or focused distribution; g. wherein the resulting contoured energy output or beams are concentric, converging electromagnetic energy beams and deposit energy dose in a localized volume of interest to treat pathologic tissue; h. wherein the conforming volume is discrete, encompassing and customized to a detrimental phase or lesion within the body, thereby enhancing restoration of control parameters to a normal physiologic range and thus enabling a healthy transition state; i. electronic or computerized controls for source and system operation with a connected power supply with cooling; and j. a medium storing computer-executable process steps to reconstruct medical images and calculate therapeutic effects of the localized non-ionizing radiation of energy treatment.

3. The device according to claim 2, further comprising: a. adjustable phased array electronics to contour different locations, shapes, sizes, frequency and timing, and other treatment related parameters of the energy output or beams; b. wherein a treatment volume can be maintained or adjusted to cover specific pathology, anatomic and functional structures or regions of interest; c. wherein a resulting adjustable radiation field size covers an internal treatment volume having diameters ranging from nanometers to a plurality of centimeters; and d. wherein a medium storing computer-executable process steps adjusts a mechanism's radiation emission for treatment and imaging.

4. The device according to claim 2, further comprising: a. antennas or interfaces for electromagnetic waves propagating in space, and electrons flowing through conductors, are connected to a transmitter; b. wherein the antennas may or may not be in a phased array; and c. overlapping directed waves build up energy deposition in a selected volume, which has been delineated beforehand by imaging or functional evaluation, to receive an enhanced dose of energy or radiation.

5. A method comprising: a. effective and deliberate targeting to non-invasively deliver non-ionizing, non-ablating electromagnetic or mechanical energy to specific volumes of tissue, locations, fluid collections, airways or microorganisms inside a body or head, wherein the energy targeting is measured and evaluated in real time with imaging, thermometry or other functional metrics; b. wherein the non-ionizing energy output is effectively directed towards a desired location, specific or selected volume, and energy waves traveling towards undesired locations, such as healthy tissue, are quenched; c. obtaining an original condition, state, conformation, functionality or phase in the body by introducing adequate localized energy to an altered process, network or system; d. wherein the energy is focused, enhanced and localized energy, and reverses prion-like mechanisms, wherein misfolded, or unfolded proteins, which may be unaggregated or aggregated, are subjected to a permissible temperature or energy dose, thereby enabling restoration to their native, normal conformation; e. counteracting environmental stresses and forces, which alter protein conformation, consisting of but not limited to, increased temperature, 38°-43° C. or greater, and reduced pH, <7.4, by inducing chaperone molecules, such as HSPs, for refolding denatured proteins and antigen presentation to dendritic cells and reversing aggregation; f. employing focused, enhanced and localized heating or other energy deposition to induce refolding itself or chaperone molecules for refolding or antigen presentation and reversing aggregation; g. inducing an effect in a diseased tissue wherein the effects comprise a combination of refolding, reversing aggregation, promoting fragmentation, enhancing degradation, elimination, enhancing immune processing and antigen presentation of peptide elements, each having a detrimental impact selected from the group consisting of misfolded proteins, their large polymers, fibrils, tangles and protein aggregates; and h. wherein the induced effects of focused, enhanced and localized energy deposition further compromise a combination of enhancing fluid circulation to repair and remove toxic metabolites in bodies, each having a diseased tissue selected from the group consisting of the CNS, the peripheral nervous system, the musculoskeletal system, the genitourinary system, the gastrointestinal system, the integument and other anatomy.

6. The method according to claim 5 wherein: a. distributing energy radiating sources, externally and around a body, including head and central nervous system, to treat and image pathologic lesions; b. radiating an energy that is non-ionizing, non-ablating electromagnetic or mechanical; c. wherein the radiated energy comprises a combination of non-ionizing output or beams selected from the group consisting of microwave radiation, radiofrequency radiation, long radio waves, laser emissions, visible, ultraviolet and solar light, infrared and far infrared light, thermal chambers, or incubators, diathermy or high-frequency electric currents, pulsed, mechanical or acoustic waves, ultrasound and high-intensity focused ultrasound (HIFU), heat from nano-devices and warm water; d. delivering the energy non-invasively without employing a device or mechanism to cut, puncture or traumatically penetrate skin or other surface, and without an open surgical procedure; e. aligning the energy-emitting sources in a localized, or circumferential, or ring or spherical distribution around a patient, as a stand-alone arrangement, or moved by a robot or a gantry, or in a surface conforming and adhering layout, as a wearable; f. employing a phased array of the non-ionizing energy sources, electronically or computer controlled, to shift and contour their output in different directions without moving the sources, for discrete and localized delivery of energy dose to a given depth or lateral position in the body with a narrow or focused distribution; g. contouring energy output or beams to concentric, converging electromagnetic energy beams and depositing energy dose in a localized volume of interest to treat pathologic tissue; h. controlling the sources electronically or with computers, and operating with a connected power supply with cooling; and i. depositing energy dose locally by shifting and contouring energy output, or beams, for treatment comprising a combination of pathologic lesions, each having a detrimental impact selected from the group consisting of infectious agents, protein misfolding, temperature and pH imbalances; cancer, cancerous and benign tumors and mass effects, demyelination, autoimmunity, loss of immunity, loss of normal mitochondrial and other organelle function; loss of neurotransmitters and neurotransmitter-degrading enzymes, vascular abnormalities and abnormal cerebral blood flow, aneurysms, atherosclerosis, arteriosclerosis, hemorrhage, blood clots, microvascular angiopathy, retinopathy, excess hemoglobin A1c, diabetic angiopathy; abnormalities of the cerebrospinal fluid (CSF) and its production and movement, hormonal imbalances, trauma and traumatic encephalopathy, mental illnesses, neuroses, addiction, depression, mania, schizophrenia and psychoses.

7. The method according to claim 6 further comprising: a. focusing the output of an array of microwave antennas to raise the temperature of a diseased volume of anatomy to levels in a range of 38°-43° C., or of a fever such as 40° C. or greater, for several seconds to 24-hour intervals; b. wherein the array is annular in a stand-alone or wearable layout; c. wherein the anatomy comprises a combination of sites selected from the group consisting of CNS, hippocampus, substantia nigra, blood-brain barrier (BBB), CSF, cranial nerves and extracranial vagus nerve fibers; d. targeting a lesion within a body by employing volumetrically discrete energy dose deposition to beneficially manipulate lesions; e. wherein the conforming, discrete volume is encompassing and customized to a detrimental phase or lesion within the body, thereby enhancing restoration of control parameters to a normal physiologic range and thus enabling a healthy transition state; f. wherein a resulting adjustable radiation field size covers an internal treatment volume having diameters ranging from nanometers to a plurality of centimeters; g. inducing hydrodynamic manipulation of intracellular or extracellular fluid with local and regional energy deposition or heating; and h. repairing, reversing or removing toxic materials and peptide aggregates from the CNS.

8. The method according to claim 7 further comprising: a. arraying microwave antennas around a pathologic site to focus and enhance microwave range energy; b. treating by applying energy to pathology selected from the group consisting of non-healing wounds, infections with microorganisms, bacteria, mycoplasma, viruses, fungi, archaea, amoebae, prions, protein misfolding, unfolding abnormalities in the proteostasis network, abnormalities in the microbiome, microorganism or bacterial signaling and quorum sensing, and biofilms; c. enhancing immunity, vascular and lymphatic flow to expedite recovery from infections and contagion throughout portions of a body selected from a group comprising the lungs, liver, gut, musculoskeletal system and CNS, the vagus, olfactory, and ophthalmic nerves and eyes and other cranial nerves, the nose, sinuses, mouth, gums and teeth; and d. modifying inflammatory reflexes linking metabolism to immune function.

9. The method according to claim 6 wherein: a. treating diseased tissue with a non-ionizing-radiation, treatment-localizing agent, wherein the agent becomes active in response to received non-ionizing-radiation energy; b. wherein the non-ionizing-radiation, treatment-localizing agents are selected from the group consisting of thermolabile or thermosensitive liposomes, which carry drugs, biologics, immune-modulating compounds, contrast agents; and microbubbles; and c. targeting a lesion within the body by employing volumetrically discrete energy dose deposition to beneficially manipulate the lesion with a therapeutic compound therein.

10. The method according to claim 5 wherein: a. defocusing the output of an array of HIFU transducers to raise the temperature of a diseased volume of anatomy to levels in a range of 38°-43° C., or of a fever such as 40° C. or greater, for several seconds to 24-hour intervals; b. wherein the array is annular in a stand-alone or wearable layout; c. wherein the anatomy comprises a combination of sites selected from the group consisting of CNS, hippocampus, substantia nigra, blood-brain barrier (BBB), CSF, cranial nerves and extracranial vagus nerve fibers; d. targeting a lesion within a body by employing volumetrically discrete energy dose deposition to beneficially manipulate lesions; e. wherein a resulting adjustable radiation field size covers an internal treatment volume having diameters ranging from nanometers to a plurality of centimeters; f. inducing hydrodynamic manipulation of intracellular or extracellular fluid with local and regional energy deposition or heating; and g. repairing, reversing or removing toxic materials and peptide aggregates from the CNS.

11. The method according to claim 5 further comprising: a. transferring energy from outside a virally or microbe infected cell, tissue, organ or body, into a volume, partly or entirely encompassing and localizing to an affected structure thereof; b. wherein a radiated energy comprises a combination of non-ionizing output or beams selected from the group consisting of microwave radiation, radiofrequency radiation, long radio waves, laser emissions, visible, ultraviolet and solar light, infrared and far infrared light, thermal chambers, or incubators, diathermy or high-frequency electric currents, pulsed, mechanical or acoustic waves, ultrasound and high-intensity focused ultrasound (HIFU), heat from nano-devices and warm water; c. delivering the energy non-invasively without employing a device or mechanism to cut, puncture or traumatically penetrate skin or other surface; d. inducing high local temperature in the encompassing volume and affected structure, in a range of 38°-43° C. or greater, therein heating subcellular organelles, cells, tissue and anatomic sites and rendering them more resistant to viral penetration and escape; e. wherein the high local temperature raises endosomal pH and inhibiting IL-6, a mediator of viral reproduction; f. wherein the high local temperature induces heat shock protein promoters, such as those of Hsp70, initiating global gene expression of antiviral proteins, thereby inactivating or counteracting virility; and g. wherein the transferred energy reduces viral replication and function.

12. The method according to claim 5 wherein: a. focusing and enhancing non-ionizing energy deposition in a body, wherein energy output is effectively directed towards a desired location, specific or selected volume; b. reversing or rectifying prion-like mechanisms in the volume, wherein misfolded, or unfolded proteins, which may be unaggregated or aggregated, are subjected to a permissible temperature or energy dose, thereby enabling restoration to their native, normal conformation; c. obtaining an original condition, state, conformation, functionality or phase in the body by introducing adequate localized energy to a deleterious altered process, network or system and thereby overcoming an undesired transition; d. wherein depositing energy into the discrete, conforming volume encompassing and customized to a detrimental phase or lesion within the body, thereby enhances restoration of control parameters to a normal physiologic range and enabling a healthy transition state; e. wherein elevated levels of mis-folded, aggregated or modified proteins, including p-Tau, are reversed and undone by restoration of lesion or core temperature; and f. wherein inhibiting pathologic modifications of proteins, including phosphorylation of tau or supplanting cold inhibition of proteasomes, yields a desired effect.

Description

BRIEF DESCRIPTION OF THE FIGURES

[0032] The construction and usage of embodiments will become readily apparent from consideration of the following specification as illustrated in the accompanying drawings, in which like reference numerals designate like parts, and wherein:

[0033] FIG. 1 is a diagram illustrating a system according to some embodiments, which stands alone and treats the head and CNS;

[0034] FIG. 2 is a simplified perspective view of arrayed microwave antennas and delivery components according to some embodiments, which stands alone and treats the body;

[0035] FIG. 3 is a diagram illustrating elements of an arrayed microwave antenna system according to some embodiments, which is a wearable and treats the head and CNS;

[0036] FIG. 4 illustrates elements of an arrayed microwave antenna system according to some embodiments, which is a wearable and treats the body;

[0037] FIG. 5 illustrates elements of an arrayed microwave antenna system, which is wearable and treats the head and CNS with an energy dose localized to a lateral position with a focused distribution; and

[0038] FIG. 6 illustrates elements of an arrayed microwave antenna system wherein the pattern of their output is effectively directed towards a desired location and energy waves traveling towards undesired locations are quenched.

DETAILED DESCRIPTION OF THE INVENTION

[0039] The construction and usage of embodiments will become readily apparent from consideration of the following specification as illustrated in the accompanying drawings, in which like reference numerals designate like parts, and wherein:

[0040] Local and Regional Energy Deposition. In the case of Alzhiemer's disease or other pathologies of the CNS, there are several therapeutic, ameliorating approaches that can be employed around the head 15 as shown in FIG. 1, or body 35 as shown in FIG. 2 with non-ionizing energy 20 of electromagnetic waves in the 300 MHz-300 GHz microwave range, or 300 kHz-300 MHz radio range, or mechanical sound waves in the 0.1 MHz-300 MHz ultrasonic range, including cavitation and boiling histotripsy. In the present invention, non-invasive, i.e., delivered without employing a device or mechanism to cut, puncture or traumatically penetrate the skin, and without an open surgical procedure, external energy 20 can be delivered to a pathological region 25 of the body 35 as shown in FIG. 2, including the head 15 and CNS as shown in FIG. 1, by the spectra and modalities including, but not limited to, the above mentioned heat, pressure and electromagnetic waves and oscillations. With these methods the mechanisms of treating disease can entail, but are not limited to, causing necrosis, induction of apoptosis, induction of heat-shock proteins, folding and unfolding proteins, increased blood, lymphatic or CSF flow, increased permeability of the blood-brain barrier (BBB) to remove toxic by-products and permit entry of beneficial effectors, initiating immune responses (stimulating or suppressing), reducing inflammation and abnormal neural stimulation, and causing euphemistic mechanical, thermal, electromagnetic or chemical interactions. By way of the present invention, non-invasive, external energy sources 10 are aimed to a focus and may employ adjustable phased array electronics to contour different locations, shapes, sizes, frequency and timing, and other treatment related parameters, of the energy output or beams with minimal or no movement of the sources. The energy is thereby concentrated in a targeted volume, enhancing it and made discrete, and therein encompassing of a detrimental lesion. A treatment volume can be maintained or adjusted, spatially and temporally, to cover specific pathology, anatomic and functional structures, or regions of interest. The resulting adjustable radiation field size covers a localized, or regional, internal volume 25 having diameters ranging from nanometers to a plurality of centimeters. A distribution of external energy radiating sources 10 may be in a localized, or circumferential distribution, or a ring 11 or spherical distribution around a patient's head 15, CNS or body 35. The patient's surface is cooled with circulating air or water 12, and may be coated with a conductive gel. The illuminated treatment volume 25 can be maintained or adjusted to cover specific pathology, anatomic and functional structures, or regions of interest. The process and time of treatment delivery may be continuous or continual via a wearable device 19, or fractionated over hours, days or weeks via a stand-alone device 11. Given the variety of energy sources possible with the present invention, they might be employed based on the efficacy of their intensity (controlled by modulating pulse-width) or frequency. The energy sources 10 are connected to a power supply 04 with cooling 05 and utilize computerized controls 01. The power supply 04, can be connected to a microcontroller to provide a means of regulating the sources' intensity and timing. The treatment system includes a computer with treatment planning software (TPS) 02, which can upload images 06 for planning and guidance, and is connected to an information system with record and verify software 03. The TPS consists of a medium storing computer-executable process steps to reconstruct medical images and calculate therapeutic effects of the localized non-ionizing radiation of energy treatment. In some configurations, the system includes a treatment table or chair, capable of movement in three dimensions, and non-invasive or invasive thermometry to measure heat in the tissue volume absorbing the delivered energy 20. In some embodiments, the system of the present invention comprises treatment of diseased tissue 25 with a non-ionizing-radiation, treatment-localizing agent 27, which becomes active in response to received non-ionizing-radiation energy 20. Such non-ionizing-radiation, treatment-localizing agents 27 include, but are not limited to, thermolabile or thermosensitive liposomes, which carry drugs, biologics, immune-modulating compounds, or contrast agents, and microbubbles.

[0041] It is an object of this invention to provide a method for depositing energy into a discrete, conforming volume encompassing and customized to a detrimental phase or lesion within a body, and thereby enhancing restoration of control parameters to a normal physiologic range, and thus enabling a healthy transition state. With the present invention, AD might be treated non-invasively, with or without pharmaceuticals, by focusing the output of an annular 11 array of microwave antennas 10, or defocusing the output of an array of HIFU transducers, to raise the temperature of a diseased tissue or volume of the CNS anatomy such as the hippocampus to levels of a fever, e.g., 40° C. or greater for several seconds to 24-hour intervals. In this manner, elevated levels of mis-folded, aggregated or modified proteins, like p-Tau, could be reversed and undone by restoration of lesion or core temperature. The desired effect could be the result of inhibiting pathologic modifications of proteins, e.g., phosphorylation of tau, or supplanting cold inhibition of proteasomes. In addition, local and regional energy deposition or heating to induce hydrodynamic manipulation of intracellular or extracellular fluid is achievable and a preferred form of delivery. For example, a larger fluid volume, greater than a discrete anatomic site such as the CSF, might be targeted to raise its temperature or oscillations and enhance the flow of CSF and the removal of toxic materials and peptide aggregates from the CNS. Heating in this localized or wider instance would enhance protein refolding and enable untangling of protein aggregates, such as Aβ or tau, as well as induce HSPs. The BBB in regions of suspected pathology could also be heated or energized therapeutically to optimize exchange of waste products and toxic metabolites or improve drug passage and delivery. If PD was being treated, the substantia nigra might be selectively heated.

[0042] Devices and Wearables. By example, in the present invention, a phased array of energy sources, such as microwave antennas, are aligned in a ring, e.g., stand-alone device 11 around a head 15 as shown in FIG. 1, or body 35 in FIG. 2, or moved by a robot or gantry, or a surface conforming and adhering layout, e.g., wearable device 19 for the head 15 demonstrated in FIG. 3 or body 35 in FIG. 4. The antennas 10, or interfaces for electromagnetic waves propagating in space, and electrons flowing through conductors, are connected to a transmitter. In some examples, the sources or antennas 10 are in a phased array, wherein they do not have to be moved. Rather, to treat pathologic lesions, the non-ionizing energy sources can be electronically or computer controlled to shift and contour their output, e.g., beams, the electromagnetic waves 20 in this instance, in different directions. Thereby, energy dose is delivered discretely and localized to a given depth or lateral position in a body 35 or head 15, illustrated in FIG. 5, with a narrow or focused distribution. The antennas 10 in this invention are distributed in an annular, ringed or spherical arrangement 11 around the body or CNS, such that the pattern of their output 20 or beams 20 is effectively directed towards a desired location, specific or selected volume 26, and energy waves traveling towards undesired locations 37 as shown in FIG. 6, e.g., healthy tissue, are quenched. The overlapping directed waves build up energy deposition in a selected volume 25, which has been delineated beforehand by imaging 06 or functional evaluation, to receive an enhanced dose of the energy or radiation. The effective and deliberate targeting to deliver non-ionizing energy to specific volumes 25 of tissue, locations 26 in FIG. 5, fluid collections, airways or microorganisms inside the body 35 or head 15 is measured and evaluated in real time with imaging, including MRI and MRI thermometry, functional MRI (fMRI) and positron emission tomography (PET), thermometry and other functional metrics. The purpose of the focused and enhanced energy deposition 25 is to reset or disable, including but not limited to: pathologic physiology or structures, nerve pathways, extracellular fluid, misfolded proteins, toxic products or microorganisms, the microbiome, disease-inducing immunity, and abnormal flow of blood, lymph, CSF, metabolites, faulty enzymology along with central and peripheral neural signals. In addition, the delivery of locally augmented energy can be used to enhance: immunity, the presence of chaperone molecules, e.g., heat shock proteins (HSPs, sHSPs), the flow of blood, lymph, CSF, metabolism, metabolites and adaptive enzymology, the delivery of energy-sensitive compounds or pharmaceuticals, carriers, and energy-sensitive vesicles, e.g., thermolabile liposomes or microbubbles.

[0043] Delivery Configurations. To deliver effective coverage and dosage with a particular energy 20 such as microwaves to a patient, distribution of emitting antennas 10 around a person facilitates spatial and temporal optimization of the treatment. A stand-alone device with emitting energy sources can move around a patient or have a ringed distribution 11 to achieve this structure. In such a geometry treatments might be given at daily, weekly or monthly intervals. Alternatively, the emitting energy sources can be attached to a patient as a wearable 19 as shown in FIG. 3 and FIG. 4, e.g., cap, bands, clothing, etc., which would permit more frequent pulsing or continual or continuous delivery of effective or initiating energy. The duty cycle with a wearable device 19 could be round-the-clock, scheduled to coincide with circadian rhythms or timed as determined to be most effective by future clinical evaluation. The duration of the heating can be seconds when high flux is employed to months when lower flux is delivered. The longer delivery times can be achieved by the device configuration that is worn by the patient, i.e., wearables 19, which can continually or continuously apply energy 20 to the zone of interest or abnormality 26.

[0044] Protein Aggregation. Misfolded proteins can aggregate and are implicated in a range of pathology including AD, PD, prion disease and cancer. The native state of the protein structure is maintained by non-covalent and disulfide bonds. These include ionic and van der waals forces. Genetic mutations, aberrant synthesis and environmental factors, e.g., abnormal temperature, pH, oxidation or aging, can destabilize bonding and native conformation resulting in protein unfolding. Unfolded or misfolded proteins, if not refolded or degraded, are susceptible to aggregation, wherein exposed hydrophobic sections may interact between proteins. These aggregates may take different forms including protein aggregates, amyloid fibrils, tangles, oligomers and degraded peptides. Refolding can take place in the presence of molecular chaperones, such as HSPs, while degradation entails elimination via the ubiquitin-proteasome system, or autophagy in lysosomes. Prions are resistant to ionizing radiation, and they do not stimulate humoral immunity, consistent with their being immunologically inert, self-encoded proteins.

[0045] HSPs, Chaperone Induction via Directed Heating. The forces by environmental stresses, e.g., increased temperature (38°-43° C. or greater), and reduced pH (<7.4), acting to alter protein conformation are counteracted in many biological systems, including mammals, by chaperone molecules. For example, HSPs engage as chaperones of unfolding proteins, and are important for refolding denatured proteins, as well as participating in antigen presentation to dendritic cells (antigen presenting cells, APCs), and eventually lymphocytes. In addition, HSPs have a role in reversing aggregation and promoting fragmentation of large polymers formed after coalescence of misfolded proteins. Therefore, when applied with therapeutic intent by way of the present invention, focused, enhanced and localized heating or other energy deposition in diseased tissue, can be employed to induce refolding itself or induce chaperone molecules, e.g., HSPs, for refolding, antigen presentation, or reversing aggregation and promoting fragmentation of large polymers formed after coalescence of misfolded proteins. The effects on detrimental peptide elements include but are not limited to: i) refolding misfolded proteins, fibrils, tangles and protein aggregates, ii) enhancing degradation and elimination of misfolded proteins, fibrils, tangles and protein aggregates, and iii) enhancing immune processing via antigen presentation of misfolded proteins, fibrils, tangles and protein aggregates, as well as, enhancing fluid circulation (see below), to repair and remove toxic metabolites in a body, including the CNS, the peripheral nervous system, the musculoskeletal system, the genitourinary system, the gastrointestinal system, the integument and other anatomy.

[0046] Non-Ionizing-Radiation, Treatment-Localizing and Enhancing Agents. Thermolabile or thermosensitive liposomes (TSLs) can enhance and localize delivery of compounds, drugs and/or imaging agents via heat-induced release at a target tissue. After intravascular infusion, the liposomes are selectively ruptured at a desired location by warming the site 25 to temperatures in the upper range of tolerated fevers, e.g., 40°-43° C. Applications include but are not limited to: imaging and therapy of cancer, localized infection, inflammatory pathologies and damaged anatomy. The chemical composition and function of TSLs have evolved (along with the heating modalities and devices employed). For example, early thermolabile liposomes were unstable because they used a single-chain lipid, but allowed quick drug release in response to a heat trigger. Better performance has been achieved with a two-chain lipid, which uses a novel phospholipid, DPPG2 (see U.S. Pat. No. 9,980,907). This TSL achieves both quick drug delivery under heat trigger and prolonged circulation absent applied heat. Its contents comprise doxorubicin, gemcitabine or a gadolinium-based contrast agent (Thermosome GmbH, Planegg, Germany). In addition to conventional chemotherapy drugs or radiographic imaging agents comprising the contents of a TSL, the present invention can use TSLs carrying immunotherapy or immune-modulating agents, including but not limited to cytokines such as, human granulocyte-macrophage colony-stimulating factor (hGM-CSF), e.g., sargramostim, Leukine (Partner Therapeutics, Inc., Lexington, Mass.). There are no presently marketed TSLs capable of carrying biologic agents or cytokines, such as GM-CSF, or recombinant proteins. When an immunotherapeutic agent is delivered with TSLs in the present invention, it is locally released by concentrating a preponderance of TSLs within a discrete targeted volume, preferably pre-treated with a modality to induce necrosis, and accessible to blood flow or cerebrospinal fluid distribution, that is heated by the present invention with concentric, converging electromagnetic energy beams in the microwave range, 300 megahertz (MHz) to 300 gigahertz (GHz). Thus, this enables systemic infusion of an immunomodulator, or other compound, but limits its interactions to a localized volume of interest. Targeting a lesion within a body by employing volumetrically discrete energy dose deposition to beneficially manipulate the lesion with a therapeutic compound therein, as recited in the present invention, compromises a treatment-localizing and enhancing agent 27. This is important in the case of inducing beneficial therapeutic effects, e.g., anti-tumor immunity with GM-CSF, where localized cytokine delivery to necrotic debris is thought to be efficacious and has been described (U.S. Pat. No. 7,481,758), while systemic distribution is not desirable since it can induce immune suppression and other side effects (Weil and Morris, unpublished). In addition, repeating mechanical waves and beams generated by ultrasound or highly-focused ultrasound (HIFU) with frequencies ranging from 0.5 mHz to 30 GHz can be brought to a focus to heat tissue and generate a heat zone to trigger the release of agents carried by TSLs, in addition to being effective modality for inducing necrosis.

[0047] Hydrodynamic Manipulation. The non-invasive delivery of localized heat to a volume of fluid, tissue or an organ involved in pathology secondary to protein aggregates offers the opportunity to invoke several reparative pathways. Heating the CSF results in the enhancement of its movement through the cerebrospinal space, which includes the subarachnoid space (between the arachnoid mater and pia mater) and the ventricular system around and inside the spinal cord and brain, including the choroid plexus, arachnoid villi and granulations, 3rd and 4th ventricles of the brain, cisterns, sulci, cauda equina and central spinal canal. Thereby it will make possible optimization of CSF flows, which are coupled to blood-flow and blood-oxygenation changes during slow-wave (non-REM) sleep, and thereby enhance removal of pathologic protein aggregates and other toxic metabolites.

[0048] Non-Healing Fractures and Wounds, Lung, Ophthalmology and Dentistry. Applied electrical stimulation is established clinically for jumpstarting repair of non-healing bone fractures and to induce wound healing following surgery or in the setting of impaired wound healing as seen in diabetic patients. The present invention of arraying microwave antennas around a pathologic site to focus and enhance microwave range energy can be employed in place of the conventional electric field stimulation in these settings. A non-healing fracture, or non-healing wound could be energized in this fashion to enhance recovery. Infection with microorganisms, including but not limited to, bacteria and associated biofilms, mycoplasma, viruses, fungi, archaea, amoebae and prions, and protein misfolding or unfolding abnormalities in the proteostasis network (PN), can similarly call up responses like a wound, which require, i) an enhanced immune response, ii) blunting of bacterial signaling, e.g., bacteria employ “quorum sensing” (by way of molecular messengers to coordinate growth and optimize uptake of nutrients and protective factors), and iii) clearance of cellular debris and biofilms. The implementation of the present invention and resulting enhancement of immunity, vascular and lymphatic flow can expedite the recovery from such infections and contagion throughout the body, including but not limited to the lungs, liver, gut, musculoskeletal system, eyes and CNS. Moreover, homeostasis of the microorganisms and integrity of the nose, sinuses, mouth, gums and teeth is maintained via pathways that can be rectified with the present invention. Thus, a degrading impact of periodontal disease on the CNS, e.g., AD or PD or neuroinflammation and prion-like mechanisms, might be corrected, and both oral and mental function restored.

[0049] Viruses. High temperature induced by transferring energy from outside a virally or microbe infected cell, tissue, organ or body, into a volume, partly or entirely encompassing and localizing to the affected structure, reduces viral replication and function, such as in the case of heating influenza virus in a range of 39°-43° C. Heating subcellular organelles, cells, tissue and anatomic sites renders them more resistant to viral penetration and escape, for example, by raising endosomal pH and inhibiting IL-6, a mediator of viral reproduction. Moreover, heat shock protein promoters, e.g., those of Hsp70, when heated to 39°-43° C., or greater, initiate global gene expression of antiviral proteins to inactivate or counteract virality.