Inhibiting neurogenic inflammation

Abstract

Neurogenic inflammation can be treated with a therapy, such as photobiomodulation (PBM), heat therapy, cold therapy, and / or electrical therapy. At least one dose of the therapy having at least one parameter setting can be generated. The dose of the therapy can be applied to one or more target nerves for a time period. The one or more target nerves include at least one or more small fibers that innervate a sensory topographical area that is currently affected and / or is prone to suffering neurogenic inflammation (e.g., contributing to arthritis). The one or more small fibers can transport information related to the neurogenic inflammation that can be blocked by the application of the therapy.

Description

INHIBITING NEUROGENIC INFLAMMATIONCross-Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Application No. 63 / 665,469, filed June 28, 2024, entitled “INHIBITING NEUROGENIC INFLAMMATION”, and U.S. Provisional Application No. 63 / 624,897, filed January 25, 2024, entitled “SYSTEMS AND METHODS TO INHIBIT NEUROGENIC INFLAMMATION BY SELECTIVE NERVE INHIBITION VIA PHOTOBIOMODULATION”. These provisional applications are hereby incorporated by reference in its entirety for all purposes.Government Funding

[0002] This invention was made with government support under NS121372 awarded by the National Institutes of Health. The government has certain rights in the invention.Technical Field

[0003] This disclosure relates generally to treatment of neurogenic inflammation and more specifically to systems and methods that can selectively inhibit neurogenic inflammation.Background

[0004] Nociceptors are a specialized class of primary afferents that respond to noxious or injurious stimuli. When stimulated by noxious or injurious stimuli, a nociceptor can cause a localized neurogenic inflammation response (in other words, inflammation generated by one or more neurons) in the topography serviced by the nociceptor. Neurogenic inflammation plays a role in many different diseases, including (but not limited to) arthritis, migraine headaches, inflammatory bowel diseases (IBD), psoriasis and other diseases of the skin, interstitial cystitis / bladder pain syndromes, chronic pain syndromes, asthma and bronchial inflammatory disease, and the like. Currently, physically cutting one or more peripheral nerves is one method for blocking and / or stopping neurogenic inflammation. Cutting the oneor more peripheral nerves can stop electrical activity that leads to the release of inflammatory factors (e.g., proteins) from the axon of the nociceptor. While it is true that cutting the one or more peripheral nerves does stop the conveyance of electrical activity that initiates a cascade resulting in neurogenic inflammation and prevents transport of inflammatory proteins from the soma to the nerve ending (synapse), cutting one or more peripheral nerves can cause severe problems. Physically cutting the one or more peripheral nerves in the associated topography is irreversible and can cause loss of wanted sensations, can create neurectomy-induced chronic pain and / or neuromas, cannot be applied in a graded manner, or the like.Summary

[0005] Neurogenic inflammation can be inhibited without physically cutting the one or more peripheral nerves in the associated topography, thereby avoiding the associated problems. Described herein are systems and methods that can inhibit neurogenic inflammation via application of a dose of therapy, such as photobiomodulation (PBM), heat therapy, cold therapy, electrical therapy (e.g., block), or the like (without cutting the one or more peripheral nerves). In some instances, the inhibition can be selective.

[0006] In an aspect, the present disclosure can include a method for selectively inhibiting neurogenic inflammation. The selective inhibition can be accomplished via use of a therapy, such as photobiomodulation (PBM), heat therapy, cold therapy (e.g., cryoneurolysis therapy), electrical therapy (e.g., block), or the like. At least one parameter for a dose of the therapy can be set and the dose can be generated having the at least one parameter. The dose can be applied to one or more target nerves for a time period. The one or more target nerves innervate a sensory topographical area that is currently affected and / or is prone to future affection by neurogenic inflammation. The one or more target nerves each include at least one or more small fibers that conduct information related to the neurogenic inflammation. The one or more target nerves can, in some instances, also include at least one larger sensory fiber that conducts other information (e.g., touch, stretch, pressure, etc.). The dose can selectively inhibit the one or more small fibers without inhibiting at least a portion of the at least one larger sensory fiber, when the at least one larger sensory fiber is present in the one or more target nerves.

[0007] In a further aspect, the present disclosure can include a method for treating arthritis caused at least in part by neurogenic inflammation. A dose of therapy, which can comprise PBM, heat therapy, cold therapy, electrical therapy (e.g., block), or the like, can be generated having at least one parameter setting. The dose of the therapy can be applied to one or more target nerves for a time period. The one or more target nerves innervate a sensory topographical area affected by arthritis caused at least in part by neurogenic inflammation. The one or more target nerves can comprise one or more small fibers that transport information related to the arthritis caused by neurogenic inflammation.

[0008] The dose of PBM, heat therapy, cold therapy, electrical therapy (e.g., block), or the like, can be generated by a specifically configured generator and the dose can be delivered by an emitter. In some instances, the emitter can be specifically configured for delivery of the dose transcutaneously, percutaneously, and / or subcutaneously. For example, the emitter can include a window, a shield, or the like. A controller can implement the generation of the certain dose.Brief Description of the Drawings

[0009] The foregoing and other features of the present disclosure will become apparent to those skilled in the art to which the present disclosure relates upon reading the following description with reference to the accompanying drawings, in which:

[0010] FIG. 1 is a block diagram showing a system that inhibits neurogenic inflammation;

[0011] FIGS. 2-5 show example implementations of the system of FIG. 1 ;

[0012] FIG. 6 shows example illustrations of how neurogenic inflammation can be inhibited using the system of FIG. 1 ;

[0013] FIG. 7 shows an example illustration of where photobiomodulation (PBM), heat therapy, and / or the like, can be applied with the system of FIG. 1 to block neurogenic inflammation;

[0014] FIG. 8 shows an example illustration of a therapy delivery device that can be used with the example of FIG. 6; and

[0015] FIGS. 9-10 are process flow diagrams showing methods for inhibiting neurogenic inflammation.Detailed DescriptionI. Definitions

[0016] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure pertains.

[0017] As used herein, the singular forms “a,” “an,” and “the” can also include the plural forms, unless the context clearly indicates otherwise.

[0018] As used herein, the terms “comprises” and / or “comprising,” can specify the presence of stated features, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and / or groups.

[0019] As used herein, the term “and / or” can include any and all combinations of one or more of the associated listed items.

[0020] As used herein, the terms “first,” “second,” etc. should not limit the elements being described by these terms. These terms are only used to distinguish one element from another. Thus, a “first” element discussed below could also be termed a “second” element without departing from the teachings of the present disclosure. The sequence of operations (or acts / steps) is not limited to the order presented in the claims or figures unless specifically indicated otherwise.

[0021] It will be understood that when an element is referred to as being "on," "attached" to, "connected" to, "coupled" with, "contacting," etc., another element, it can be directly on, attached to, connected to, coupled with or contacting the other element or intervening elements may also be present. In contrast, when an element is referred to as being, for example, "directly on," "directly attached" to, "directly connected" to, "directly coupled" with or "directly contacting" another element, there are no intervening elements present. It will also be appreciated by those of skill in the art that references to a structure or feature that is disposed “adjacent” another feature may have portions that overlap or underlie the adjacent feature.

[0022] As used herein, the term “neurogenic inflammation” can refer to a localized inflammation caused by nociceptor activation. Nociceptor activation can cause the release of inflammatory factors (e.g., one or more inflammatory proteins (e.g., HMGB1 , or the like), neuropeptides (e.g., substance P, calcitonin gene related peptide (CGRP), prostanoids, or the like.), proinflammatory cytokines, or the like) toinitiate an inflammatory reaction. Nociceptor release can also trigger rapid plasma extravasation and edema, contributing to pain conditions.

[0023] As used herein, the term “therapy” can refer to the delivery of one or more stimuli or agents to a neural structure to at least partially inhibit neurogenic inflammation. Types of therapy can include, but are not limited to, light therapy (such as photobiomodulation (also referred to as PBM)), temperature-based therapy (e.g., heat therapy or cold therapy), magnetic therapy, pharmaceutical therapy, or the like.

[0024] As used herein, the term “photobiomodulation”, abbreviated as “PBM”, can refer to the delivery of light signal(s) at one or more prescribed wavelengths and dosing schemes to provide non-ionizing optical radiation to a site including a predefined target area within a patient’s body to achieve a desired physiological response (e.g., to stop neurogenic inflammation). PBM utilizes non-ionizing light sources, including lasers, light emitting diodes, and / or broadband light sources and can be delivered by one or more optical emitters. In some examples, the light can have a wavelength between 250 nm and 1600 nm. As another example, the wavelength can be in the visible range (e.g., from 400 nm to 700 nm) and / or nearinfrared range (e.g., from 700 nm to 1100 nm) of the electromagnetic spectrum. As a further example, the wavelength can be between 500 nm and 1064 nm. It is noted that at 1064 nm the effect of melanin absorption can be ignored.

[0025] As used herein, the term “heat”, also referred to as “heat therapy”, can refer to the therapeutic application of one or more heat signals to at least a portion of the body of a patient (including one or more target nerves) that results in an increase in tissue temperature. Heat therapy can be applied by the same optical emitter(s) as the photobiomodulation and / or a separate heat mechanism (e.g., another optical emitter, a radio frequency (RF) ablation tool, a focused ultrasound, a resistive heating device, or the like). For example, heat therapy can include the use of one or more wavelengths of infrared light of 1300 nm or larger.

[0026] As used herein, the term “dose” can refer to a quantity and / or an intensity of a treatment and a duration of the treatment to be given at one time. In some instances, the dose can, additionally or alternatively, be at least partially defined by a wavelength or other parameter of the therapy.

[0027] As used herein, the term “nerve” can refer to a bundle of fibers that send messages from parts of the body to the brain, spinal cord, or ganglia and / or viceversa in the form of electrical signals. For example, a nerve can be a sensory nerve that includes sensory fibers, a motor nerve that includes motor fibers, a sensorimotor nerve that includes sensory and motor fibers, etc. As another example, a nerve can be an enteric nerve that includes enteric fibers.

[0028] As used herein, the term “fiber” can refer to an axon, which is a long slender projection of a nerve cell or neuron in vertebrate organisms having a diameter that corresponds to conduction velocity. Generally, a fiber conducts electrical impulses transmitting information in one or more directions throughout the body and is classified depending on the type of fiber (e.g., sensory, motor, etc.), the diameter of the fiber and / or if myelin coating is present.

[0029] As used herein, the term “sensory fiber(s)” can refer to part of the peripheral nervous system (PNS) that conduct electrical impulses between a part of the body experiencing sensation and the brain / spinal cord. Sensory fibers have a range of fiber sizes. For example, sensory fibers can be classified as Acx (diameter 13-20 pm, conduction velocity 80-120 m / s, myelinated, associated with muscle spindle fibers and Golgi tendon organ); Ap (diameter 6-12 pm, conduction velocity 33-75 m / s, myelinated, associated with all cutaneous mechanoreceptors); A8 (diameter 1 -5 pm conduction velocity 3-30 m / s, thinly myelinated, associated with free nerve endings of tough and pressure, nociceptors of the neospinothalamic tract, cold thermoreceptors); and C (diameter 0.2-1 .5 pm, conduction velocity 0.5-2.0 m / s, unmyelinated, associated with nociceptors of the paleospinothalmic tract and warmth receptors). A “small” sensory fiber can refer to an AS fiber and / or a C fiber. As an example, C fibers can be associated with neurogenic inflammation.

[0030] As used herein, the term “nociceptor” can refer to a sensory receptor that sends signals to the brain to produce the sensation of pain in response to noxious stimuli. As an example, nociceptors can be associated with neurogenic inflammation.

[0031] As used herein, the term “dosing scheme” can refer to a schedule of one or more doses of PBM (e.g., quantities of light of one or more wavelengths), heat, or the like, to be delivered to a target area of a patient per a unit of time for a length of time.

[0032] As used herein, the term “patient” can refer to any warm-blooded organism, including, but not limited to, a human being, a pig, a rat, a mouse, a dog, a cat, a goat, a sheep, a horse, a monkey, an ape, a rabbit, a cow, etc. The terms patient and subject can be used interchangeably herein.II. Overview

[0033] Neurogenic inflammation is triggered by activation of nociceptors in a topology resulting in at least neuropeptide release. Such nociceptor activation can contribute to conditions like arthritis, migraine headaches, inflammatory bowel disease, psoriasis, dermatologic diseases, interstitial cystitis, bladder pain syndrome, chronic pain syndromes, asthma, bronchial inflammatory diseases, peripheral neuropathy, multiple sclerosis, chronic obstructive pulmonary disease, allergic rhinitis, hypertension, atherosclerosis, gastroesophageal reflux disease, endometriosis, dry eye syndrome, traumatic nerve injury, or the like. Neurectomy of one or more peripheral sensory nerves has emerged as a way to block neurogenic inflammation and treat any one of the conditions. While physically cutting the one or more peripheral nerves via neurectomy can stop the neurogenic inflammation if the polypeptides are released from the nerve ending (synapse) after transport from the soma that is triggered by electrical activity, physically cutting the one or more peripheral sensory nerves has several notable problems. The notable problems include loss of wanted sensation (e.g., touch sensation), neurectomy-induced chronic pain and / or neuromas, irreversibility, and the like. Moreover, the release of the neuropeptide may not be triggered by electrical activity. As an alternative to a drastic neurectomy, one or more doses of photobiomodulation (“PBM”), heat therapy, cold therapy (e.g., cryoneurolysis), electrical therapy (e.g., block), and / or the like can be used to selectively inhibit neurogenic inflammation. The one or more doses of PBM, heat therapy, cold therapy (e.g., cryoneurolysis), electrical therapy (e.g., block), and / or the like can act similarly to a neurectomy without causing the negative side effects of neurectomy and can be applied in a graded manner (e.g., with partial or full effect).III. Systems

[0034] Inhibition of neurogenic inflammation can be achieved without physically cutting the one or more peripheral nerves involved in the neurogenic inflammation. Instead, the system 100 of FIG. 1 can inhibit neurogenic inflammation by at leastpartially silencing conduction in one or more nerve fibers, such as nociceptors, that play a part in neurogenic inflammation by applying one or more doses of a “therapy” (e.g., photobiomodulation (PBM), heat therapy, cold therapy (e.g., cryoneurolysis), electrical therapy (e.g., block), and / or the like). It should be noted that PBM generally refers to the delivery of light, at one or more prescribed wavelengths and one or more dosing schemes, to at least one nerve within and / or near a target area (referred to as, one or more “target nerves” with one or more small fibers, such as c fibers and / or nociceptors, that can be selectively inhibited) to achieve a desired physiological response (at least partially stopping and / or lessening neurogenic inflammation). Heat therapy generally refers to the therapeutic application of one or more heat signals (e.g., IR, RF, or conduction-based heat signals) to at least a portion of the body of a patient (e.g., one or more target nerves or fibers within a nerve) to increase a temperature of the at least the portion of the body of the patient to achieve the desired physiological response. Cold therapy generally refers to application of one or more cooling elements to lessen or block neural transmission in a target nerve. For instances, cryoneurolysis can selectively block A8 fibers via freezing in a manner similar to RF ablation. Electrical therapy (e.g., block) generally refers to the therapeutic application of one or more electrical signals (e.g., direct current, pseudo direct current, and / or high frequency alternating current waveforms) to at least a portion of the body of the patient (e.g., at least the one or more target nerves or fibers with the nerve) to at least partially block conduction in the one or more target nerves and to block nociceptors and / or neurogenic inflammation associated with nociceptors. In certain instances, pharmaceutical therapy may also be used and can refer, for example to the application of one or more chemical compounds (such as capsaicin) to compromise or “prune” nociceptors. Notably, in some instances, the therapy can be reversible, but may be made irreversible if desired, and can be selective such that application of the therapy does not cause a patient to experience unwanted sensation and / or induce additional chronic pain and / or neuroma(s).

[0035] Referring now to FIG. 1 , the system 100 can include a therapy device 102 that can be coupled to a generator 104 (in a wired and / or wireless connection), which can in turn be coupled to a controller 106 (in a wired and / or wireless connection) to configure and apply the therapy. Example implementations of thesystem 100 are shown in further details in FIGS. 2-5. The controller 106 can include at least a non-transitory memory (e.g., memory) 108 that can store instructions and a processor 110 that can execute the instructions for the therapy. Optionally, the controller 106 can have an input 112 (e.g., a sensor, a user interface such as a keyboard, mouse, touch screen, button(s), or the like for accepting data, instruction modification, dosing information, or the like) and / or an output 114 (e.g., a visual display, a speaker, a haptic feedback device, or the like for communicating data, dose information, feedback, instructions for use, or the like). The input 112 and the output 114 are shown external to and in communication (wired and / or wireless) with the controller, but either or both can be embodied in a same device as the controller. Also optionally, the controller 106 can communicate with an external device 116 (e.g., mobile device, computer, or the like) that can be used as an input 112, an output 114, and / or any other functions described in more detail below.

[0036] Generally, the controller 106 can configure at least one dose of the therapy based on information related to the therapy (optionally, at least a portion of the information related to the therapy can be received through the input 112 and / or from the external device 116). Multiple doses of therapy can be applied over time according to a dosing schedule and / or prescription. For example, the treatment for arthritis may need to be applied once or twice a day, one or a few times per week, or one or several times per month, depending on the parameters used and the response for a given patient. The information related to the therapy can include, but is not limited to, sensor information (e.g., conduction information), a manual input from a user (e.g., due to the user feeling pain, paresthesia, or another response), a dosing scheme prescribed by a medical professional, and / or the like. The one or more doses of therapy can include at least one of an amount of light, heat, cold, electrical signal, or the like, to be applied for a time. In some instances, two or more doses of therapy can be applied (with the same and / or different parameters). In some instances, the one or more doses of therapy can include multiple therapeutic types (e.g., heat and cold, light and heat, light and electrical signal, cold and heat and light, or the like in any type of combination (e.g., in sequence, overlapping, etc.).

[0037] The controller 106 can control the configuration of the one or more doses by setting at least one parameter for a dose of the therapy. The at least one parameter of the dose of the therapy can include, but is not limited to, the amount oflight, heat, cold, electrical signal, or the like, the time of application, the number of doses, the wavelength(s) of light and / or the electrical signal, the power of the light, the heat, the cold, and / or the electrical signal, if the light, the heat, the cold, and / or the electrical signal is applied in a continuous and / or pulsatile manner, a power density, a total energy or the like. For instance, the dose of therapy can have at least one wavelength between 500 nm and 1200 nm (e.g., for PBM, for instance within 10 nm or less of 1064 nm) or between 1000 nm and 3000 nm (e.g., for heat therapy). For example, a dose of heat therapy can be configured (based on the at least one parameter) to cause an increase in the temperature at the target nerve and / or nerve fiber (e.g., nociceptor) of between 1 and 120 degrees C, 1 and 100 degrees C, or the like, for at least the time period of application, depending on the duration of application. In another example, a dose of electrical block therapy can include a direct current waveform (e.g., to selectively block a small neuron) or a pseudo direct current waveform, and / or a high frequency alternating current (e.g., to block a pain sensation). In some instances, the controller 106 can configure the one or more dose of therapy (e.g., PBM therapy) to silence conduction in at least one small diameter sensory nerve fiber for a period of time extending after the dose of therapy is applied. The controller 106 can also and / or alternatively configure the at least one parameter of the dose of therapy to provide varying onset and / or recovery timeframes for the silencing of the one or more small diameter fibers (e.g., at least one small diameter sensory nerve fiber) where larger doses might be used to extend the effects for longer periods of time and / or affect fibers of increasing diameter compared to those initially affected.

[0038] In some instances, the controller 106 can be in wired and / or wireless communication with the external device 116 to transfer data and / or instructions therebetween. Although not illustrated, the external device 116 can include at least a processor, and optionally a user interface, a display, or the like and can be, for example, a smart phone, a tablet, a computer, medical device, or the like, that can at least provide input to and / or receive a signal from the controller 106. In some instances, the external device 116 and / or the controller 106 can include a power source. In some instances, the external device 116 can be the “controller” of system 100 and the controller 106 can relay data and instructions from the external device 116 through the generator 104 to the therapy device 102. In some instances, theexternal device 116 can be an external computer connected to an electronic medical recording (EMR) system and can create a log for the patient's EMR regarding a dose of therapy applied to the patient. The logged details can include, for example, the wavelength, power, spot size, duration, beginning / ending time, thermal measurement(s), optical image(s) of the target nerve for reference, the total number of doses applied, or the like.

[0039] As previously noted, the controller 106 can be in electrical communication (wired and / or wireless with the generator 104 to generate the dose of therapy having the at least one parameter. The generator 104 can receive the configuration of the at least one parameter of the dose of the therapy and generate a signal reflecting the configuration of the dose of the therapy. The signal generated by the generator 104 can then be communicated to the therapy device 102 (by a wired and / or wireless connection). After receiving the signal, the therapy device 102 can apply the dose of the therapy having the at least one parameter to the one or more target nerves and / or nerve fibers of the user (e.g., the patient) for the time period of the dose. The one or more target nerves and / or nerve fibers of the target nerve(s) can innervate a sensory topographic area that is affected and / or is prone to being affected in the future by neurogenic inflammation. For example, the one or more target nerves can include one or more small fibers that conduct information related to the neurogenic inflammation and at least one larger sensor fiber that conducts touch information. The dose of the therapy having the at least one parameter can selectively inhibit the one or more small fibers without inhibiting at least a portion of the at least one larger sensory fiber. The therapy device 102 can apply the therapy to at least partially silence conduction in the one or more small fibers within one or more target nerves. It should be noted that application of the therapy by the system 100 can at least partially silence conduction in the one or more small fibers for a period of time longer than the time of application of the therapy (e.g., the silencing can begin based on the dose and can last for one or more hours, days, weeks, or months after the dose of PBM, the heat, the cold, the electrical signal, or the like, is applied).

[0040] The therapy device 102 can be positioned to deliver the therapy to at least a portion of a patient’s body. For example, the portion of the patient’s body can include one or more target nerves (each having at least one small diameter fiber thatcan have its conduction at least partially inhibited.)- For instance, the at least one small diameter fiber can be a c fiber and / or a nociceptor. The one or more target nerves (and / or at least one small diameter fiber within the one or more target nerves) can innervate a sensory topographical area affected by a disease or condition, like arthritis. Neurogenic inflammation from the one or more target nerves (and / or the at least one small diameter fiber within) can contribute to arthritis pain, headache pain, or the like. Inhibition of the at least one small diameter fiber can reduce neurogenic inflammation (and thereby the pain feeling) by disrupting axonal transport of inflammatory factors that cause the neurogenic inflammation and / or inhibiting release of the inflammatory factors that cause the neurogenic inflammation.

[0041] The therapy device 102 can apply PBM, heat therapy, cold therapy, electrical block therapy or the like. For example, the therapy device 102 can include at least two electrodes for electrical block therapy. As another example, the therapy device 102 can include at least one optical emitter that can provide PBM and / or heat therapy. For heat therapy, the therapy device 102 can alternatively and / or additionally include a radio frequency (RF) ablation tool, a focused ultrasound, a resistive heating device, an infrared (IR) laser, or the like, for applying the heat therapy. When the therapy device 102 is an IR laser the heat therapy can, for example, be provided by wavelengths of light between 1000 and 3000 nm. When the therapy device 102 provides a focused ultrasound, then ultrasonic energy can be delivered to generate focal heat in targets below the surface of the skin or in deeper tissues. When the therapy device 102 is an RF ablation tool the tool can include at least one RF antenna that can deliver RF energy. For cold therapy, the therapy device 102 can alternatively and / or additionally include at least one of: ice, at least one ice pack, cold water (e.g., above freezing but considered cold to the human body), one or more phase change materials, at least one Peltier device, cooling sprays, at least one cryogen delivery system, at least one evaporative cooling system, at least one microfluidic cooling system, at least one solid-state heat sink, at least one magnetocaloric effect causing system, at least one chemical cooling system, or the like.

[0042] For PBM therapy, the at least one optical emitter can deliver light from non-ionizing light sources, including lasers, light emitting diodes, and / or broadband light sources. In some examples, the light can have a wavelength between 250 nmand 1600 nm. As a further example, the wavelength can be in the visible range (e.g., from 400 nm to 700 nm) and / or near-infrared range (e.g., from 700 nm to 1100 nm) of the electromagnetic spectrum. As an additional example, the wavelength can be between 500 nm and 1064 nm. It is noted that at 1064 nm the effect of melanin absorption can be ignored. The therapy device 102 can apply the dose of therapy continuously for a time period and / or two or more times during a time period (e.g., in a pulsatile manner). It should be noted that in some instance the same therapy device 102 (which can include one or more therapy source(s)) and / or a single therapy source can be utilized for providing multiple therapies at different times (e.g., heat and PBM, electrical and heat, or the like). It should also be understood that while a single therapy device 102 is shown and predominantly described, the therapy device can be more than one therapy device - e.g., at least two separate devices for applying heat, cold, PBM, and / or electrical therapy doses. For instance, a single therapy device 102 and / or two separate therapy devices can provide cooling therapy and then heating therapy to reduce the threshold for inducing small fiber inhibition. For example, an appropriate dose of cold (e.g., cold that can cause a temperature decrease of the target nerve between 1 °C and 15°C for a time) and then an appropriate dose of heat (e.g., heat that can cause a temperature increase of the target nerve between 1 °C and 15°C for a time) can be administered to one or more nerves that serve at least a portion of the sensory topography of the area that is or could be affected by neurogenic inflammation to reduce or prevent the neurogenic inflammation by inhibiting the small fiber neurons, such as nociceptors, so that the nociceptors cannot participate actively in a neuroinflammatory response for at least a time. While not wishing to be bound by theory, it is considered that smaller temperature decreases or increases (e.g., 1°C or less, 2°C or less, 3°C or less, 5°C or less, 10°C or less, or the like) may enable longer durations of cold or heat to be applied without causing undesirable tissue and / or neural damage (e.g., frostbite, blisters, nerve damage, etc.). Greater temperature changes (e.g., lower cooling temperatures and / or higher heat temperatures) (e.g., 10°C -20°C changes, 10°C - 15°C changes, or the like) can be delivered for a shorter duration to avoid causing undesirable damage. In some instances, smaller doses (e.g., smaller temperatures changes and / or shorter application times) can be applied to create a block that lasts only while heat is applied. In other instances, application of a cold dose and thenapplication of a heat dose can create blocks that persist beyond the time the application of the heat dose is ended (e.g., 1 second, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 1 day, or the like after).

[0043] The therapy device 102 can apply the dose of the therapy transcutaneously, percutaneously, and / or subcutaneously to the one or more target nerves for the time period. At least a portion of the therapy device 102 can be positioned at a location beneath, at, or near the patient’s skin relative to the one or more target nerves. For instance, the therapy device 102 can be positioned to directly contact a portion of the one or more target nerves, to be in direct communication with a portion of the one or more target nerves (e.g., no intervening tissue), or to be in communication with the one or more target nerves through intervening tissue. In some instances, at least a portion of the therapy device 102 can be within the body and the remainder of the therapy device 102 can be external to the patient’s body. In another instance, the entire therapy device 102 can be within the body (e.g. held and / or implanted) or external to the body (e.g., held or worn on the body). The general location of the at least one target nerve may be known and the therapy device 102 can be positioned near the general location. The position enables the therapy device 102 to facilitate delivery of the therapy to the target nerve. The therapy device 102 can be in wired and / or wireless communication with at least the generator 104. In some instances, if the generator 104 is within the controller 106, the therapy device 102 can be in wired and / or wireless communication and the controller 106. It should be noted that the at least one parameter of the dose of the therapy can be set at least partially based on the positioning of the therapy device 102 (e.g., amount of intervening tissue, type of intervening tissue, etc.).

[0044] The generator 104 also can be in wired and / or wireless communication with the controller 106. In some instances, at least a portion of the generator 104 can be within the controller 106. In other instances, the generator 104 at least a portion of the generator 104 can be within the therapy device 102. In still other instances, the generator 104 can be independent from the controller 106 and the therapy device 102. The generator 104 can be external to the patient’s body. The controller 106 can be external to the patient’s body. The controller 106 can include at least a non-transitory memory (e.g., memory 108) to store instructions and dataand a hardware processor (e.g., processor 110) to execute one or more of the instructions. In some instances, the controller 106 can received a feedback signal (e.g., from the therapy device 102, an input 112, or the like) after delivery of the therapy. In some instances, a single dose of the therapy can at least partially stop and / or lessen the neurogenic inflammation. However, in other instances, multiple doses of the therapy (which may have the same or different at least one parameter) are required to at least partially stop and / or lessen the neurogenic inflammation. In still other instances, the system 100 can be used to at least partially stop and / or lessen the neurogenic inflammation for a trial period of time (e.g., several hours, days, or weeks) to estimate whether a fully implantable system would be effective as a chronic therapy for a given patient before incurring the surgical burden and expense of implanting a chronic fully implantable system to at least partially stop and / or lessen neurogenic inflammation. In such instances, the system 100 can be external and enable trialing a therapy before moving forward with an implantable version of system 100.

[0045] As previously noted, FIGS. 2-5 show example implementations 200-500 of the system 100 of FIG. 1 . It should be understood that while the example implementations 200-500 of FIGS. 2-5 are meant to be illustrative, the examples in FIGS. 2-5 are not meant to be limiting. Each of FIGS. 2-5 have a generator 104 and a controller 106, and each of FIGS. 2-5 has a uniquely configured therapy device 202, 302, 402, and 502 respectively. Additional optional elements of FIG. 1 are not shown, but it will be understood that the controller 106 can be in communication with one or more of the optional elements.

[0046] Referring now to FIG. 2, illustrated is a therapy device 202 (e.g., a transcutaneous device) that can be configured to deliver the therapy through a window 204 formed under the skin of the user (e.g., patient) and through obstructive material. Example obstructive materials can include tissues such as bone (e.g., bone of a skull, bone of a sternum, bone of a spine, etc.), muscle, fat, or the like and / or foreign objects such as metal plates or other surgically implanted materials. Although the skin generally is not considered a significant obstruction for light to pass through, the skin can provide a small level of obstruction of light, which can be detrimental to dosage schemes of the therapy that deliver smaller amounts of therapy. The obstructive material can absorb the therapy and dimmish the efficacyof treatment with the therapy. The window 204 can be created and / or implanted in at least a portion of the obstructive material in line with at least a portion of the one or more target nerves (or other neural structure). The window 204 allows the therapy to be delivered to the one or more target nerves and to pass only through the skin and the window before the therapy reaches the target nerve. In other words, the therapy device 202 can deliver the therapy to the target nerve through the window without obstruction due to the obstructive material. The therapy device 202 and the window 204 can be configured to align for ease of application of the therapy (e.g., through a magnetic and / or mechanical alignment mechanism).

[0047] In FIG. 3, at least a portion of therapy device 302 (e.g., a subcutaneous device) can enter the body under the skin through a surgical opening. The surgical opening can be a cut through obstructive material and / or intervening tissue. The surgical opening can allow the therapy device 302 easier access to the one or more target nerves. In other words, the surgical opening can cut away light modulating intervening tissues and occlusive materials, such as muscle, bone, fat, skin, implanted materials, etc. The therapy device 302 can be any shape that can at least partially extend an application portion through the surgical opening towards the one or more target nerves. The therapy device 302 can be positioned near the one or more target nerves (as shown) or can be in direct contact with the one or more target nerves (not shown). The therapy device 302 can be used before, during, or after a surgery. The therapy device 302 that can be inserted through a surgical opening can be particularly useful for directly visualizing the one or more target nerves.

[0048] In some instances, the therapy device 302 can be connected to a shield 304 that can protect a user or another person holding the therapy device from at least a portion of the PBM and / or heat therapy (e.g., one or more wavelengths that can harm the eyes, excess heat, or the like). The shield 304 can extend outward from a portion of the therapy device 302 (in some instances, the shield 304 can extend radially around the therapy device 302) to attach to and / or be placed in contact with the surgical opening or a location remote from the surgical opening (e.g., skin surrounding the surgical opening). The shield 304 can be removable from the therapy device 302 in some instances. In other instances, the shield 304 can be part of the therapy device 302. The shield 304 can be any shape and / or material that can contain at least a portion of the therapy (e.g., the material may include glassand / or one or more polymers that can be processed to maintain transparency but that include one or more dyes to make the shield 304 at least partially opaque to specific wavelengths and / or intensities).

[0049] Referring now to FIG. 4, illustrated is a therapy device 402 (e.g., a percutaneous device) that is configured to deliver the therapy through the skin (and potential obstructive material) to the target nerve. The therapy device 402 can be held above the skin, pushed into the skin, and / or built into a wearable device (e.g., a bracelet type device, a bandage type device, or the like). In some instances, the therapy device 402 can be connected to a shield 404. The shield 404 can be built into the therapy device 402 or can extend outward from the therapy device 402 (in some instances, the shield 404 can extend radially around the therapy device 402 and can eliminate the need for safety glasses) to attach to and / or be placed in contact with the patient’s skin. The shield 404 can be removable from the therapy device 402 in some instances. In other instances, the shield 404 can be part of the therapy device 302. The shield 404 can be any shape and / or material that can contain at least a portion of the therapy (e.g., the material may include glass and / or one or more polymers that can be processed to maintain transparency but that include one or more dyes to make the shield 404 at least partially opaque to specific wavelengths and / or intensities).

[0050] Referring now to FIG. 5, illustrated is a therapy device 502 (e.g., a fully implanted therapy device) that is configured to deliver the therapy to the target nerve. The therapy device 502 can be implanted under the skin. The generator 106 can also be implanted under the skin (as shown), but in other instances me be external to the skin. The therapy device 502 and / or the implanted generator 106 may each be implanted at least partially in contact with obstructive material / intervening tissue, between different types of obstructive material / intervening tissue, above obstructive material / intervening tissue, or below obstructive material / intervening tissue depending on the type of therapy and / or the target nerve. In some instance the obstructive materials / intervening tissues between the skin and the target nerve can be at least partially removed. The therapy can be delivered directly to the target nerve, with direct contact between the target nerve and the therapy device 502, and / or with intervening tissue between the therapy device and the target nerve. The generator 106 is shown implanted with the therapy device 502 and in electricalcommunication with the therapy device. The controller 104 can communicate wirelessly with the generator 106 (as shown) and / or the therapy device 502 (not shown). In at least some instances, the implanted therapy device 502 can be particularly positioned by medical personnel for improved application of the therapy directly towards the target nerve. Implanting the therapy device 502 (and the generator 106) can remove at least the skin barrier from attenuating the therapy, and can in some instances at least partially remove barriers posed by obstructive materials / intervening tissues, such as muscle, fat, bone, etc. The controller 104 can be external for better control of the therapy.

[0051] FIG. 6 shows example illustrations (A, B, C) of normal nociceptor conduction and function, conduction and function with neurogenic inflammation, and conduction and function with therapy applied to block neurogenic inflammation. Illustration A shows normal conduction and function through a peripheral nociceptor, where normal sensation(s) is conducted to the spinal cord. The nucleus within the soma has the ability to generate neuropeptides (also referred to as inflammatory factors, like inflammatory proteins (e.g., HMGB1 )) but has not released the neuropeptides from the nucleus yet or may not have produced the neuropeptides yet. In illustration B, the neurogenic inflammation condition involves the nucleus within the soma generating neuropeptides (also referred to as inflammatory factors, like inflammatory proteins (e.g., HMGB1 )) that are released from the soma and conducted to the source of the pain, causing or increasing neurogenic inflammation. Normal sensation signal(s) are still conducted to the spinal cord, and small fibers conduct a pain signal. However, as shown in illustration C, while not wishing to be bound by theory, when a therapy (e.g., PBM and / or heat therapy) is applied, the generation and conduction of the neuropeptides is stopped and / or their movement is blocked. This can effectively halt the progression of the neurogenic inflammation. Notably, the dose of therapy can also selectively inhibit the one or more small fibers, not only by disrupting conduction of action potentials, which can block conduction of the pain signal, and also because the soma is not depolarized, prevent or reduce the release of inflammatory factors from the nucleus and / or soma. Additionally, while these disruptions of nociceptor activity happen at least one larger sensory fiber can continue to conduct (at least partially) normal sensation information (e.g., touch, information, pressure information, stretch information, etc.).

[0052] As an example, the therapy can be applied to treat neurogenic inflammation related to arthritis of the hand. FIG. 7 shows an example illustration of therapy application locations for arthritis of the hand. At least an application end of the therapy device (e.g., of FIGS. 1 -5) can be applied at the target locations to block neurogenic inflammation related to arthritis. For example, the one or more target nerves can be related to the median nerve and / or the palmar ulnar nerve and the target locations can be over at least a portion of the median nerve and / or the palmar ulnar nerve. FIG. 8 shows an illustration of an example therapy delivery device (that can include all or part of system 100) and can be positioned on the skin of the wrist (e.g., pushed into the skin) over the target locations to apply light therapy (e.g., PBM and / or heat). The example therapy delivery device can, optionally, provide guidance to locate the target locations in the wrist, such as shown in elements A and B, where stimulation is applied to let the user know whether the target has been located. The target locations can be identified, for example, by electrical mapping, optical mapping, landmark mapping, or the like. As shown in element C, the therapy can be applied to the target location through the skin and any intervening tissues to at least partially halt and / or stop neurogenic inflammation related to arthritis of the hand. A similar approach, at associated target locations, may be used for halting and / or stopping neurogenic inflammation related to migraine headaches, inflammatory bowel disease, psoriasis, dermatologic diseases, interstitial cystitis, bladder pain syndrome, chronic pain syndromes, asthma, and / or bronchial inflammatory diseases.IV. Methods

[0053] Another aspect of the present disclosure can include methods (FIGS. 9- 10) for inhibiting neurogenic inflammation via photobiomodulation (PBM), heat therapy, cold therapy, electrical therapy (e.g., block), and / or the like. It should be understood that neurogenic inflammation can be associated with conditions like arthritis, migraine headaches, inflammatory bowel disease, psoriasis, dermatologic diseases, interstitial cystitis, bladder pain syndrome, chronic pain syndromes, asthma, bronchial inflammatory diseases, peripheral neuropathy, multiple sclerosis, chronic obstructive pulmonary disease, allergic rhinitis, hypertension, atherosclerosis, gastroesophageal reflux disease, endometriosis, dry eye syndrome,traumatic nerve injury, or the like. The methods can be executed by a system, e.g. system 100 of FIG. 1 in any implementation like those shown in FIGS. 2-5 and 8.

[0054] For purposes of simplicity, the methods are shown and described as being executed serially; however, it is to be understood and appreciated that the present disclosure is not limited by the illustrated order as some steps could occur in different orders and / or concurrently with other steps shown and described herein. Moreover, not all illustrated aspects may be required to implement the method, nor is the method necessarily limited to the illustrated aspects.

[0055] Referring now to FIG. 9, illustrated is a method 800 for inhibiting neurogenic inflammation. At 802, a dose of therapy (e.g., PBM, heat therapy, cold therapy, electrical therapy (e.g., block), or the like) can be generated (e.g., by a generator 104) having at least one parameter. The at least one parameter of the dose of therapy can be set by a controller (e.g., controller 106). The at least one parameter can include, but is not limited to the amount of light, heat, cold, electrical signal, or the like, the time of application, the number of doses, the wavelength(s) of light and / or electrical signal, the power of the light, heat, cold, electrical signal, or the like if the light, heat, cold, and / or electrical signal is applied in a continuous and / or pulsatile manner, a power density, a total energy or the like. For instance, the dose of therapy can have at least one wavelength between 500 nm and 1200 nm (e.g., for PBM) or between 1000 nm and 3000 nm (e.g., for heat therapy, which can cause a heat increase at the target nerve of between 1 and 120 degrees C, 1 and 100 degrees, or the like, depending on the duration of application). In another instances, the dose of therapy can be an electrical therapy (e.g., block) and can include a direct current waveform and / or a high frequency alternating current waveform. At 804, the dose of therapy can be applied (e.g., by therapy device 102, transcutaneously, percutaneously, or subcutaneously) to one or more target nerves for a time period. The dose can be delivered in a continuous fashion, in a discrete fashion one at a time (at different times), or in a pulsatile fashion. For example, the one or more target nerves can innervate a sensory topographical area affected by a disease or condition, like arthritis, caused by and / or causing neurogenic inflammation. The one or more target nerves can include one or more small fibers that transport information related to neurogenic inflammation and at least one larger sensory fiber that conducts other information (e.g., touch information, pressure information, stretchinformation, or the like). It should be understood that the at least one larger fiber may also be a motor fiber and / or an autonomic fiber. The neurogenic inflammation is promoted by and / or includes at least one inflammatory factor, which may be an inflammatory protein, like HMGB1 (when the neurogenic inflammation is caused by at least some forms of arthritis). Application of the dose of therapy can selectively inhibit the one or more small fibers not only by disrupting conduction of action potentials, but by disrupting axonal transport of the at least one inflammatory factor while not disrupting, if present, at least one larger sensory fiber conducting other information (e.g., touch information, pressure information, stretch information, or the like). When trying to stop neurogenic inflammation related to arthritis of the hands, for instance, the one or more target nerves can be the medial nerve, the palmar ulnar nerve, the radial nerve, and / or the dorsal ulnar nerve.

[0056] Referring now to FIG. 10, illustrated is another method 900 for inhibiting neurogenic inflammation. At 902, at least one parameter for a dose of therapy (e.g., PBM, heat therapy, cold therapy, electrical therapy (e.g., block), or the like) can be set (e.g., by controller 106). The at least one parameter can include, but is not limited to the amount of light, heat, cold, electrical signal, or the like, the time of application, the number of doses, the wavelength(s) of light and / or an electrical signal, the power of the light, heat, cold, electrical signal, or the like, if the light, heat, cold, and / or electrical signal is applied in a continuous and / or pulsatile manner, a power density, a total energy or the like. As an example, the parameter can be automatically determined (e.g., in a closed loop where the system includes and / or is in communication with one or more sensors and / or schedules stored in memory) or input manually (e.g., in an open loop). At 904, the dose of therapy having the at least one parameter can be generated (e.g., by generator 104). Then the dose of therapy can be applied (e.g., by therapy device 102) to one or more target nerves for a time period. The one or more target nerves innervate a sensory topographical area that is currently affected and / or is prone to future affection by neurogenic inflammation and the one or more target nerves each include one or more small fibers that conduct information related to the neurogenic inflammation and, in some instances, at least one larger sensory fiber that conducts touch information (or stretch and pressure information, in the case of the bowel, or other information in the cases of other organs). It should be understood that application of the dose oftherapy selectively inhibits one or more small fibers (e.g., conduction of an electrical signal and / or release / conduction of inflammatory factors) without inhibiting at least a portion of the at least one larger sensory fiber. The dose can be delivered in a continuous fashion, in a discrete fashion one at a time (at different times), or in a pulsatile manner. Multiple doses of therapy can be applied over time according to a dosing schedule and / or prescription. For example, the treatment for arthritis may need to be applied once or twice a day, one or a few times per week, or one or a few times per month, depending on the parameters used and the response for a given patient.

[0057] For example, an appropriate dose of cold (e.g., cold that can cause a temperature decrease of the target nerve between 1°C and 15°C for a time) and then an appropriate dose of heat (e.g., heat that can cause a temperature increase of the target nerve between 1 °C and 15°C for a time) can be administered to one or more nerves that serve at least a portion of the sensory topography of the area that is or could be affected by neurogenic inflammation to reduce or prevent the neurogenic inflammation by inhibiting the small fiber neurons, such as nociceptors, so that the nociceptors cannot participate actively in a neuroinflammatory response for at least a time. While not wishing to be bound by theory, it is considered that smaller temperature decreases or increases (e.g., 1°C or less, 2°C or less, 3°C or less, 5°C or less, 10°C or less, or the like) may enable longer durations of cold or heat to be applied without causing undesirable tissue and / or neural damage (e.g., frostbite, blisters, nerve damage, etc.). Greater temperature changes (e.g., lower cooling temperatures and / or higher heat temperatures) (e.g., 10°C -15°C changes, 10°C - 20°C changes, or the like) can be delivered for a shorter duration to avoid causing undesirable damage. In some instances, smaller doses (e.g., smaller temperatures changes and / or shorter application times) can be applied to create a block that lasts only while heat is applied. In other instances, application of a cold dose and then application of a heat dose can create blocks that persist beyond the time the application of the heat dose is ended (e.g., 1 second, 1 minute, 5 minutes, 10 minutes, 30 minutes, 1 hour, 1 day, or the like, after).

[0058] From the above description, those skilled in the art will perceive improvements, changes, and modifications. Such improvements, changes andmodifications are within the skill of one in the art and are intended to be covered by the appended claims.

Claims

The following is claimed:1 . A method comprising: setting at least one parameter for a dose of photobiomodulation (PBM), heat therapy, cold therapy, and / or electrical therapy; generating the dose of PBM, heat therapy, cold therapy, and / or electrical therapy having the at least one parameter; and applying the dose of the PBM, heat therapy, cold and / or electrical therapy to one or more target nerves for a time period, wherein the one or more target nerves innervate a sensory topographical area that is currently affected and / or is prone to future affection by neurogenic inflammation and the one or more target nerves each include one or more small fibers that conduct information related to the neurogenic inflammation, wherein the one or more small fibers are at least partially inhibited by the PBM, heat therapy, cold therapy, and / or electrical therapy.

2. The method of claim 1 , wherein the one or more small fibers comprise c fibers and / or nociceptors and the one or more target nerves further comprise at least one sensory fiber conducting other information at least partially not inhibited by the dose of therapy.

3. The method of claim 1 , wherein the dose of the PBM, heat therapy, cold therapy, and / or electrical therapy inhibits the one or more small fibers that cause the neurogenic inflammation by disrupting axonal transport of at least one inflammatory factor that contributes to the neurogenic inflammation and / or inhibiting release from a nucleus or a soma of the at least one inflammatory factor that contributes to the neurogenic inflammation.

4. The method of claim 3, wherein the at least one inflammatory factor comprises at least one inflammatory protein.

5. The method of claim 4, wherein the inflammatory protein comprises HMGB1 .

6. The method of claim 1 , wherein the neurogenic inflammation is related to arthritis, migraine headaches, inflammatory bowel disease, psoriasis, dermatologic diseases, interstitial cystitis, bladder pain syndrome, chronic pain syndromes, asthma, bronchial inflammatory diseases, peripheral neuropathy, multiple sclerosis, chronic obstructive pulmonary disease, allergic rhinitis, hypertension, atherosclerosis, gastroesophageal reflux disease, endometriosis, dry eye syndrome, and / or traumatic nerve injury.

7. The method of claim 1 , wherein the applying the dose of the PBM, heat therapy, cold therapy, and / or electrical therapy further comprises applying the dose of the PBM, heat therapy, cold therapy, and / or electrical therapy transcutaneously, percutaneously, and / or subcutaneously to the one or more target nerves for the time period.

8. The method of claim 1 , wherein the at least one parameter comprises a power density, and / or a total energy.

9. The method of claim 1 , wherein the dose of the PBM comprises one or more wavelengths and between 500 and 1200 nm.

10. The method of claim 1 , wherein the neurogenic inflammation is related to arthritis of the hand.11 . The method of claim 10, wherein the one or more target nerves is related to the median nerve and / or the palmar ulnar nerve.

12. The method of claim 1 , wherein the applying is repeated two or more times during the time period.

13. The method of claim 1 , wherein the applying is continuous for the time period.

14. The method of claim 1 , wherein the dose of the PBM, heat therapy, cold therapy and / or electrical therapy is heat therapy.

15. The method of claim 14, wherein the method further comprises determining the at least one parameter of the dose based on a temperature rise of the one or more target nerves between 1 and 120 degrees C for the time period.

16. The method of claim 14, wherein the applying is done by an IR laser, an RF ablation tool, a focused ultrasound, and / or a resistive heating device.

17. The method of claim 14, wherein the applying is done by an IR laser, wherein the IR laser is configured to provide wavelengths of light are between 1000 and 3000 nm.

18. A method comprising: generating a dose of therapy, wherein the therapy comprises photobiomodulation (PBM), heat therapy, cold therapy, and / or electrical therapy having at least one parameter setting; and applying the dose of the therapy to one or more target nerves for a time period, wherein the one or more target nerves innervate a sensory topographical area affected by arthritis caused at least in part by neurogenic inflammation, wherein the one or more target nerves comprise one or more small fibers that transport information related to the arthritis caused by neurogenic inflammation.

19. The method of claim 18, wherein the information related to the arthritis contributed to by neurogenic inflammation comprises at least one inflammatory factor, and wherein the one or more target nerves further comprise at least one larger sensor fiber that conducts other information and the dose of the therapy selectively inhibits the one or more small fibers by disrupting axonal transport of the at least one inflammatory factor and / or inhibits release of the at least one inflammatory factor from a nucleus and / or a soma while allowing the at least one larger sensory fiber to conduct the other information.

20. The method of claim 18, wherein the one or more target nerves are related to the median nerve and / or the palmar ulnar nerve.

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