Patent Grant
12296129
The present technology relates generally to stimulus-based therapeutic devices, systems, and methods. In particular, the disclosure relates to systems and methods for applying heat pulses and topical compounds to a patient's body for therapeutic purposes.
In 1965, Melzack and Wall described the physiologic mechanisms by which stimulation of large diameter non-pain sensory nerves could reduce the amount of unpleasant activity carried by pain nerves. This landmark observation published in Science was termed the “gate control theory” and offered a model to describe the interactions between various types of the sensory pathways in the peripheral and central nervous systems. The model described how non-painful sensory input such as mild electrical stimulation could reduce or “gate” the amount of nociceptive (painful) input that reached the central nervous system. The gate-control theory stimulated research that lead to the creation of new medical devices and techniques, such as transcutaneous electrical nerve stimulators (TENS). However, TENS and other techniques evolving from the gate control theory have provided sub-optimal pain relief. Accordingly, new techniques for reducing pain are needed.
The present technology is directed generally to systems, devices, and associated methods for applying stimuli to various parts of the body of a human subject or patient. The stimuli can be configured to activate thermoreceptors in the human subject to alleviate, mask, or otherwise reduce a sensation of pain. The stimuli can be a thermal stimulus, such as heat. The stimuli can also be a composition configured to activate certain thermoreceptors, such as menthol or capsaicin.
Several details describing thermal and electrical principles are not set forth in the following description to avoid unnecessarily obscuring embodiments of the present technology. Moreover, although the following disclosure sets forth several embodiments of the present technology, other embodiments can have different configurations, arrangements, and/or components than those described herein without departing from the spirit or scope of the present technology. For example, other embodiments may have additional elements, or they may lack one or more of the elements described in detail below with reference to
The terminology used in the description presented below is intended to be interpreted in its broadest reasonable manner, even though it is being used in conjunction with a detailed description of certain specific embodiments of the present technology. Certain terms may even be emphasized below; however, any terminology intended to be interpreted in any restricted manner will be overtly and specifically defined as such in this Detailed Description section. Additionally, the present technology can include other embodiments that are within the scope of the claims, but are not described in detail with respect to
Reference throughout this specification to “one embodiment” or “an embodiment” means that a particular feature, structure or characteristic described in connection with the embodiment is included in at least one embodiment of the present technology. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features or characteristics may be combined in any suitable manner in one or more embodiments.
Reference throughout this specification to relative terms such as, for example, “substantially”, “approximately”, and “about” are used herein to mean the stated value plus or minus 10%.
The terms used herein are not intended—and should not be taken—to exclude from the scope of this present technology other types of heat sources that are designed to be placed on the skin to enable pain relief. Illustrative embodiments will be shown and described; however, one skilled in the art will recognize that the illustrative embodiments do not exclude other embodiments.
The headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed present technology.
In the illustrated embodiment, the stimulus pod 110 includes a battery 155, a circuit board 160, a charging coil 165, and several housing elements 170 (individually referred to as an upper cover 170a and a body 170b). The battery 155 can power the stimulus surface and the circuit board 160. The battery 155 can be a lithium polymer battery or another suitable battery type. The charging coil 165 can be configured to receive power from a power source (e.g., a charging station) and deliver the power to the battery 155. In some embodiments, the stimulus pod 110 can include a wireless communication link 175 through which the stimulus pod 110 receives instructions and/or sends data to and from a control station. In some embodiments, the control station can be a mobile application contained on a cell phone. The housing elements 170 can enclose the internal components of the stimulus pod 110 and provide a convenient handling surface.
In some embodiments, as described in greater detail below with reference to
In some embodiments, multiple ones of the stimulus pods 110 can be used in concert at different places on the patient's body. In some embodiments, the stimulus pods 110 can also be used to deliver medicine to a patient through electrophoresis, iontophoresis, and/or heat-enhanced perfusion due to capillary dilation. Electrophoresis is the motion of dispersed particles relative to a fluid under the influence of a spatially uniform electric field. Electrophoresis is ultimately caused by the presence of a charged interface between the particle surface and the surrounding fluid. Iontophoresis (a.k.a., Electromotive Drug Administration (EMDA)) is a technique using a small electric charge to deliver a medicine or other chemical through the skin. It is basically an injection without the needle. The technical description of this process is a non-invasive method of propelling high concentrations of a charged substance, normally a medication or bioactive agent, transdermally by repulsive electromotive force using a small electrical charge applied to an iontophoretic chamber containing a similarly charged active agent and its vehicle. One or two chambers are filled with a solution containing an active ingredient and its solvent, also called the vehicle. The positively charged chamber (anode) will repel a positively charged chemical, whereas the negatively charged chamber (cathode) will repel a negatively charged chemical into the skin.
Referring to
Referring to
Referring to
Referring to
The stimulus pod 110 can be attached to (e.g., secured against, retained by, etc.) the anchor 120 such that the stimulus surface 150 is secured against the patient's skin.
Referring to
Referring to
Referring to
Referring to
Referring to
Referring to
Any of the attachment mechanisms illustrated in
During operation of the system 100, multiple ones of the stimulus pods 110 can be interchanged between different ones of the anchors 120, and vice versa. A patient can use a stimulus pod 110 until the battery is depleted, and then simply swap in another stimulus pod 110 with a fresh battery. The attachment means can be strong enough and the dimensions of the stimulus pod 110 can be small enough that the stimulus pod 110 can be worn under the patient's clothing easily. The placement of the anchors 120 can vary greatly according to a predetermined diagnostic pattern or personal preference. In some embodiments, one or more of the stimulus pods 110 can be placed at an area of discomfort, such as a painful lower back. Some research suggests that placing additional stimulus pods 110 at an area remote from a problem area can also provide analgesic effects. For example, a patient may place one of the stimulus pods 110 at the lower back—where their pain is—but they can also use a second one of the stimulus pods 110 near the shoulders or on the legs. Multiple stimulus pods 110 can be used in concert to produce an aggregate affect. Because different areas of the human body have different nerve densities, in certain areas two of the stimulus pods 110 placed near one another can be perceived as a single, large stimulus pod. For example, the patient's back has much lower nerve density than the face, neck, or arms. Accordingly, the patient can use a pair of small stimulus pods 110 (e.g., one or two inches in diameter) at the lower back and spaced about three or four inches apart to achieve the same sensory result as a larger stimulus pod covering the entire area. An unexpected benefit of this arrangement is that much less power is required to provide the stimulus in two small areas than would be required to stimulate the entire area.
In the illustrated embodiment, the stimulus pod 110 also includes a stimulus cycle switch 206 configured to, for example, switch between different levels of an applied stimulus (e.g., a low, medium, or high temperature). The stimulus pod 110 can also include indicators 208A-C such as LEDs that can light up in response to a particular setting of the stimulus cycle switch 206. In other embodiments, a single indicator 208 capable of changing its color, intensity, or other property can be used to indicate different settings of the stimulus pod 110. A push-type stimulus cycle switch 206 is illustrated in
The stimulus pod 110 may also include an electrical circuit and a temperature measuring element configured to monitor the temperature of the skin. The temperature measuring element may be positioned, for example, in the center of the stimulus surface 150. The temperature measuring element may be operatively coupled to the electrical circuit, and the electrical circuit may be communicatively coupled to a monitoring/control device such as a desktop or laptop computer, a smartphone, a tablet, or other device. The electrical circuit may sense, via the temperature measuring element, a temperature of the skin and, based off the sensed temperature and/or other information, determine one or more characteristics of the skin. The electrical circuit may then transmit information about the one or more characteristics to the monitoring/control device, and the monitoring/control device may display the information to a user or health professional. For example, the electrical circuit may determine information about the skin's thermal transfer capacity and/or the skin's blood flow and send this information to the monitoring/control device for display. The electrical circuit may also utilize a look-up table, formula, chart, or other source of information to predict when thermal injury to the skin may occur. When the electrical circuit determines thermal injury may occur, the electrical circuit may instruct the monitoring/control device to provide a warning to the user, and/or may automatically turn the stimulus pod 110 off.
In some embodiments, one or more of the stimulus pods 110 can communicate with a control station to, for example, coordinate the delivery of stimulation to a patient at one or multiple locations.
The control station 230 can be a desktop or laptop computer, a smartphone, a tablet, or other device. In some embodiments, the control station 230 can be included with or integrated into a charging station, and/or can share components such as a power source, circuitry, etc., with a charging station. The control station 230 can instruct one or more of the stimulus pods 110 to apply heat, electric stimuli, vibration, or other stimulus or combination of stimuli in various patterns to the patient's body. In other embodiments, the pods 110 include a button or series of buttons through which the pods 110 can be manually operated. The possible applications are many, and include various combinations of ramp up operations, maximum intensity operations (e.g., maximum temperature or maximum electrical current, etc.), ramp down operations, stimulus soak operations, and lockout period operations (e.g., as described in detail below with reference to
In several embodiments, the control station 230 can detect or receive information regarding the location of the stimulus pods 110 on the patient's body, and can vary the stimulus pattern accordingly. In one embodiment, the stimulus pods 110 can be built with certain body positions in mind. In some embodiments, the stimulus pods 110 can carry body position labels to instruct the patient to apply the stimulus pods 110 according to the label. For example, in a set of four stimulus pods, two can be marked “shoulders,” a third can be marked “lower back,” and a fourth can be marked “upper back.” In some embodiments, the anchors 120 can communicate their location to the stimulus pod 110. For example, the anchors 120 can include passive identifiers such as RFID tags or other simple, passive devices for communicating with the stimulus pods 110 and/or the control station 230. In such embodiments, the anchors 120 can remain in place even when different stimulus pods 110 are swapped in and out of the anchors 120. Therefore, the stationary anchors 120 can accurately provide location information to the control station 230 independent of which specific ones of the stimulus pods 110 occupy the anchors 120.
In other embodiments, the patient can inform the control station 230 where the stimulus pods 110 are situated, and with this information the control station 230 can apply the desired stimulus pattern to the stimulus pods 110. For example, the stimulus pods 110 can fire sequentially, and the patient can indicate the location of the stimulus on a user interface. Through the user interface, the patient can also operate the system 100 and apply treatment. In some embodiments, the control station 230 can graphically display a depiction of the patient's body, and the patient can indicate to the control station 230 where the stimulus pods 110 are located on their body. Alternatively, the patient can directly control the stimulus application through the stimulus pods 110 by moving a pointing device along the graphical depiction of their body to create a virtual stimulus-massage that the patient, or a healthcare professional, controls directly. In some embodiments, the control station 230 can include a touch screen that the patient can touch to apply heat or other stimulus to various portions of their body (or to the body of another patient).
In some embodiments, the index pod 110a and the control station 230 can discern when two or more of the stimulus pods 110 (e.g., dummy pods 110b or index pods 110a) are near enough to one another that they can work in aggregate. If the control station 230 knows where the stimulus pods 110 are placed on the patient's body, the control station 230, through the index pod 110a, can vary the threshold distance between the stimulus pods 110 as a function of nerve density at different locations on the body. For example, if the control station 230 discerns that two or more of the stimulus pods 110 are three inches apart and on the lower back, the control station 230 can operate those ones of the stimulus pods 110 together to effectively cover the area between the stimulus pods 110 as well as the area directly contacting the stimulus pods 110. By comparison, if two or more of the stimulus pods 110 are three inches apart, but are placed on a more sensitive area, such as the patient's face or neck, the control station 230 can determine that the aggregate effect may not be perceived to reach the area between those ones of the stimulus pods 110 because of the greater nerve density. This information can be used when applying a treatment plan that calls for stimulus on a prescribed area. In some embodiments, the control station 230 can determine whether one of the stimulus pods 110 is on or near the prescribed area, and if not, whether the aggregate effect from two or more of the stimulus pods 110 can be used to carry out the treatment plan, and can execute the plan through the stimulus pods 110.
Sensory information is carried to the brain via two adjacent spinothalamic tracts: the anterior spinothalamic tract and the lateral spinothalamic tract. The anterior spinothalamic tract conducts information about pressure and crude touch. The lateral spinothalamic tract conducts information about pain and temperature. More specifically, the lateral spinothalamic tract conducts information about pain and temperature via A-Δ, A-β, and C nerve fibers. A-Δ and A-β fibers are myelinated and therefore have fast conduction velocities. C nerve fibers are unmyelinated and therefore have slower conduction velocities. Accordingly, an initial sensation of pain is likely due to transmission of signals via A-Δ and A-β fibers, while lingering sensations of pain are likely due to transmission of signals via C fibers.
Pain signals, transmitted by A-Δ and C nerve fibers, activate awareness in the brain to a potential threat. Pain relief comes when the brain concludes there is no longer a need for the sensation. Pain sensations lasting long after typical healing times (i.e., chronic pain) or for no apparent reason (i.e., idiopathic pain) indicates there may be problems with the immune system, underlying neuropathic disorders, and/or underlying psychological disorders. If the chronic pain is caused by problems with the body's immune system, the pain may be caused by the affected portions of the body being poorly repaired, thereby causing continued firings of the C-fibers transmitting pain sensations. Alternatively, the affected portions of the body may have been re-injured at some point, resulting in continued firings of the C-fibers. If the chronic pain is caused by neuropathic disorders, the pain may be caused by defective nociceptors firing in the absence of inflammatory signals, defective C-fibers transmitting signals without nociceptor activation, a defective dorsal horn continuing to signal the brain without C-fiber signals, or receiving cells in the thalamus being unable to turn down the threat level. If the chronic pain is caused by a psychological disorder, the pain may be the result of other parts of the brain/mind stimulating the thalamus to continue pain sensation production.
The present technology includes systems and methods for applying a stimulus configured to activate warm and/or cold thermoreceptors of a subject, thus providing pain relief. For example, the stimulus may be heat, and the stimulus delivery systems described herein can be used to apply the heat to a patient. In another example, other heat sources beyond those explicitly described herein may be used to apply the therapeutic stimuli to the patient. In yet another example, the therapeutic stimuli may be a topical compound such as capsaicin or menthol. Applying a stimulus in the form of heat and/or topical compounds can reduce a wide variety of pain and/or treat a variety of ailments. At least a portion of this stimulation-induced pain relief may result from the activation and/or desensitization of warm and/or cold thermoreceptors.
To better appreciate the benefits of the present technology, it is helpful to understand the body's reaction to heat. The human body is generally sensitive to heat, with certain body parts having a higher sensitivity than other body parts. The body's sensitivity to heat is recognized by thermoreceptors located in the skin and subcutaneous tissue.
The thermoreceptors located throughout the body can be excited or activated at different temperatures.
1. Cold and Warm Thermoreceptors
Thermoreceptors may be divided into at least two categories: cold receptors and warm receptors. Unsurprisingly, cold receptors differ from warm receptors. Warm receptors, for example are stimulated by normothermic temperatures (e.g., about 33-38° C.) and by warm to hot temperatures (e.g., 38° C. or higher). Activation of heat receptors are also affected by the rate of rise of the heat stimuli. As temperatures increase from 40° C. onward, stimulation of warm receptors may produce significant analgesia. However, as temperature continues to increase, warm receptors produce pain, warning the body about potentially harmful burns. The amount of analgesia produced by warm receptors is based on a number of factors, including absolute temperature, rate of temperature rise, duration of heating, and individual variations. Warm receptors utilize myelinated A-Δ fibers and unmyelinated C-fibers and thus exhibit varying conduction times.
Cold receptors are stimulated by cool and cold temperatures (e.g., 33° C. or less), thus providing the sensation of cold and, with extreme low temperatures, a warning about potential tissue damage. Despite also being activated by cold temperatures, certain populations of cold receptors can “awaken” and be stimulated by warm temperatures near the range of uncomfortable heat in a phenomenon described as paradoxical cold. For example, some cold receptors can be activated by temperatures of about 40° C. or higher, about 41° C. or higher, about 42° C. or higher, about 43° C. or higher, about 44° C. or higher, about 45° C. or higher, about 46° C. or higher, about 47° C. or higher, about 48° C. or higher, and/or about 49° C. or higher. This paradoxical stimulation of cold fibers by high-level temperatures may offer the body additional warning and protection from potentially damaging levels of energy.
In addition to being activated at different (yet overlapping) temperatures, cold receptors further differ from warm receptors. For example, cold receptors are generally associated with A-Δ fibers that exhibit conduction rates of up to 30 m/sec, which is much faster than warm C fibers' 2 m/sec. The faster conduction of cold sensation may further provide additional protection from potentially damaging levels of energy. In addition, the density of cold receptors is much greater than that of warm receptors. For example, in an exemplary human forearm, there are approximately 7 cold receptors to every 0.24 warm receptors per square centimeter.
2. Transient Receptor Potential Channels (TRP)
There are different types of cold receptors and warm receptors. The transient receptor potential channel (TRP) superfamily, for example, includes structurally related, non-selective cation channels that serve a variety of functions in the peripheral and central nervous systems, including temperature sensation. In the peripheral nervous system, TRPs respond to a number of different stimuli, including temperature, pressure, inflammatory agents, and receptor activation. In the central nervous system, TRP activity may promote neurite outgrowth, coordinate receptor signaling, and induce excitotoxic cell death resulting from noxious stimuli. Accordingly, the diverse functionality of TRP channels make them an intriguing yet difficult therapeutic target.
The TRP superfamily includes a number of related channels. A functional subset of the channels is distinguished by their sensitivity to temperature. For example, temperature-sensitive TRPs include melastatin receptors (e.g., the menthol receptor TRPM8), vanilloid receptors (e.g., the capsaicin receptor TRPV1 and other heat related receptors TRPV2, TRPV3, and TRPV4), and the chemical, temperature, and mechanical stress sensor ankyrin 1 (TRPA1). In combination, these channels (collectively referred to as thermoTRPs) cover a broad range of temperatures, ranging from noxiously hot to dangerously cold.
The vanilloid receptors, TRPV1 (line 1206), TRPV2 (line 1208), TRPV3 (line 1210), and TRPV4 (line 1212), are all generally activated by warm and/or hot temperatures (e.g., greater than about 30° C., greater than about 35° C., greater than about 40° C., etc.). Similar to TRPM8 and TRPA1, these heat-associated thermoTRPs may be associated with certain types of pain, including, for example, muscle pain (e.g., strained or pulled muscle), headache, nerve pain, joint pain, idiopathic pain, and/or chronic pain. Accordingly, and as discussed below in more detail, certain aspects of the present technology include targeting TRPV1, TRPV2, TRPV3, and/or TRPV4 to reduce pain.
To better understand certain embodiments of the present technology, it may be helpful to further understand the interplay between certain thermoreceptors. In particular, TRPV1 and TRPM8 may play an important role in thermally mediated pain reduction and will therefore be discussed in further detail herein.
A. TRPV1
TRPV1 is a protein that is expressed in sensory neurons and plays a role in both thermal sensation and nociception. TRPV1 was first identified by its responsiveness to capsaicin, a vanilloid derived from chili peppers that elicits a burning sensation. TRPV1 also responds to noxious heat, with an activation threshold of approximately 43° C. and a temperature coefficient of Q10>20. TRPV1 may also be activated by extracellular acidification, indicating it may act as a polymodal nociceptor integrating multiple forms of noxious stimuli. TRPV1 also responds to other pungent chemicals and endogenous lipid-derived molecules, many of which act cooperatively to stimulate channel activity. For instance, capsaicin and acidification both can lower the heat activation threshold for channel activation. TRPV1 is expressed in approximately 30-50% of all somatosensory neurons in rodent models, predominantly peptidergic C-fiber nociceptors. Knockout studies have confirmed that TRPV1 plays a role in nociception. For example, TRPV1 knockout mice and isolated DRG cells of TRPV1 knockout mice demonstrate significant impairments in the detection of noxious heat and protons along with complete loss of capsaicin sensitivity, indicating TRPV1 plays an important role in detection of heat in addition to nociception.
In certain conditions, TRPV1 may become sensitized and/or overactive. The sensitization and overactivity of TRPV1 can be associated with many different forms of pain. Sensitization of TRPV1 may occur via coupling with second messenger signaling cascades by a variety of proalgesic and proinflammatory agents, including nerve growth factor (NGF), bradykinin, lipids, prostaglandins, and ATP. Furthermore, TRPV1 activity contributes to neurogenic inflammation in which nociceptors themselves release inflammatory mediators, thus acting autonomously to promote inflammation and hyperalgesia. TRPV1 may also be required for development of inflammatory thermal hyperalgesia, demonstrating an essential role for TRPV1 in pain hypersensitivity associated with chronic pain conditions. In sum, TRPV1, and in particular TRPV1 hyperactivity, can be integrally involved in many different chronic pain conditions.
TRPV1 activity is associated with numerous types of inflammation and inflammatory-related pain. For example, an increase in the number of TRPV1 immunoreactive fibers in inflamed skin correlates with inflammatory hyperalgesia. Furthermore, TRPV1 antagonists may inhibit thermal and/or mechanical hypersensitivity associated with multiple models of inflammation, including UVB-evoked pain and sensitization, complete Freund's adjuvant (CFA)-induced pain, post-operative pain, and/or cancer pain. Moreover, nocifensive behavior may be significantly reduced in TRPV1 knockout animals or via treatment with TRPV1 antagonists. TRPV1 was also found to mediate pain induced by the activation of the inflammatory mediator protease-activated receptor-2 (PAR2). Thermal hyperalgesia associated with ischemic pain may also be dependent on TRPV1.
TRPV1 may also be functionally significant in neuropathic pain conditions. For example, TRPV1 expression may increase following nerve injury, while blockade of TRPV1 function may reduce both thermal and/or mechanical hypersensitivity. Chemotherapeutics such as oxaliplatin or paclitaxel can increase TRPV1 sensitivity, suggesting an instructive role in chemotherapy-induced peripheral neuropathy. Desensitization of TRPV1 may provide relief from osteoarthritis, postoperative pain, and nerve injury-induced heat sensitivity, further supporting an involvement of TRPV1 in both in inflammatory and neuropathic pain.
Because of the role of TRPV1 in pain, TRPV1 antagonists configured to inhibit the activation of TRPV1 have shown some promise in treating patients with neurogenic and/or inflammatory diseases. But TRPV1 antagonists have significant obstacles. For example, common side effects of TRPV1 antagonists include loss of noxious heat sensation, increased burn risk, and hyperthermia. Moreover, due to the systemic nature of many TRPV1 antagonists, these side effects may not be restricted to a localized area, thereby exacerbating their effects.
Accordingly, another potential mechanism recognized in the present disclosure is to treat pain by desensitizing TRPV1 receptors. Most sensory modalities undergo adaptation or desensitization to a stimulus following prolonged or repeated exposure to the stimulus. Adaptation or desensitization may cause a decreased activity or response despite the continuous presence of the stimulus. The more prolonged and extreme the desensitization, the less active the receptor will be.
TRPV1 may be susceptible to desensitization. Activation of TRPV1 leads to a Ca2+ influx into nociceptive sensory neurons. This Ca2+ influx depolarizes the membrane and prompts the release of proinflammatory neuropeptides from primary afferent nerve terminals. However, prolonged or repeated activation of TRPV1 may result in excessive Ca2+ influx, preventing the channel from resetting itself and thus leading to the desensitization of TRPV1. In a desensitized state, TRPV1 will no longer be active, even in the presence of TRPV1 agonists or stimuli. Therefore, repeated or prolonged activation of TRPV1 may provide pain relief by desensitizing TRPV1. As will be discussed in detail below, the present technology includes particular methods configured to maximize the recruitment of TRPV1 to maximize the therapeutic effect following desensitization. For example, applying a pulsing heat stimulus to a pain producing region of a patient can cause repeated activation of TRPV1, thereby leading to excessive Ca2+ influx, TRPV1 desensitization, TRPV1 deactivation, and pain relief.
B. TRPM8
TRPM8, also known as the cold and menthol receptor 1 (CMR1), is a protein that is encoded by the TRPM8 gene and expressed in sensory neurons. TRPM8 is the primary molecular transducer of cold somatosensation in humans. For example, mice lacking functional TRPM8 gene expression are severely impaired in their ability to detect cold temperatures. Remarkably, these animals are deficient in many diverse aspects of cold signaling, including cool and noxious cold perception, injury-evoked sensitization to cold, and cooling-induced analgesia.
As discussed previously,
TRPM8 is an ion channel, which, upon activation, allows Na+ and Ca2+ ions to enter the cell, leading to depolarization and the generation of an action potential. The signal is conducted from primary afferents (type C and A-A), eventually leading to the sensation of cold and cold pain. In contrast to the TRPV1 (capsaicin) receptor, which is potentiated by low pH, acidic conditions inhibit the TRPM8 Ca2+ response to stimuli. Thus, the TRPV1 and TRPM8 receptors may act together in response to inflammatory conditions: TRPV1, by proton action, increases the burning sensation of pain, while the acidity inhibits TRPM8 to block the more pleasant sensation of coolness in more dire instances of pain.
Like with TRPV1, TRPM8 may be associated with many causes of pain. For example, TRPM8 upregulation in bladder tissues correlates with pain in patients with painful bladder syndromes, and TRPM8 is upregulated in many prostate cancer cell lines. However, low concentrations of TRPM8 agonists such as menthol may be antihyperalgesic in certain conditions (e.g., reducing sensitivity to pain), but high concentrations of TRPM8 agonists may cause both cold and mechanical hyperalgesia (e.g., increased sensitivity to pain). TRPM8 knockout mice not only indicated that TRPM8 is required for cold sensation but also revealed that TRPM8 mediates both cold and mechanical allodynia in rodent models of neuropathic pain. Therefore, TRPM8 antagonists may be effective in reversing established pain in neuropathic and visceral pain models.
TRPM8 may be susceptible to both sensitization and desensitization. TRPM8 sensitization increases the sensation of cold and/or cold pain, also known as cold hyperalgesia. For example, applying 40% L-menthol to the forearm results in increased sensitization to the menthol stimulus. An A fiber conduction blockade of the superficial radial nerve reduces the menthol-induced sensation of cold and hyperalgesia. This likely occurs because blocking A fiber conduction results in inhibition of a class of group C nerve fiber nociceptors needed to transduce the sensation of pain. Thus, menthol may sensitize cold-sensitive peripheral C nociceptors and activate cold-specific A-Δ fibers under certain circumstances.
However, TRPM8 may also experience desensitization following prolonged or repeated exposure to cold and/or to menthol. For example, after initial sensitization to menthol exposure, TRPM8 response to menthol may decline over time. This desensitization may be a result of, for example, the influx of Ca2+ into the cell following activation, which in turn causes a reduction in excitability of TRPM8. For example, TRPM8 channels may show decreasing activity during cold or menthol application in the presence of extracellular Ca2+.
The TRPM8 receptor may work in conjunction with the TRPV1 receptor to maintain a feasible threshold temperature range in mammalian cells. For example, the perception of stimulation of TRPM8 and/or TRPV1 occurs at the spinal cord and brain, which integrates signals from different fibers of varying sensitivity to temperature to produce a thermal sensation.
C. Cross Desensitization of TRPV1 and TRPM8
Cold and warm receptors may also exhibit cross desensitization. For example, TRPV1 and TRPM8 may cross desensitize following the prolonged exposure to at least one of the receptors' agonists. As discussed previously, TRPV1 may desensitize following prolonged exposure to heat, capsaicin, or another TRPV1 activating agent, and TRPM8 may desensitize following prolonged exposure to heat, cold, menthol, or another TRPV1 activating agent. Additionally, prolonged menthol exposure may desensitize TRPV1 (via cross-desensitization) and prolonged capsaicin exposure may desensitize TRPM8 (via cross-desensitization). Cross-desensitization may also occur in channels following repeated and prolonged exposure to heat.
D. Clinical Significance of TRPV1 and TRPV8
As discussed herein, cold receptors such as TRPM8 can begin signaling warnings at temperatures of 40° C. Warm receptors, such as TRPV1, maximize signaling at approximately 40-49° C. Thus, exponential recruitment of both warm and cold receptors occurs between higher temperatures such as 40° C. to 49° C.
Despite this, traditional heat therapies operate at temperatures of 40° C. or less because prolonged exposure to heat above 40° C. may lead to tissue damage. Yet, as described herein, the primary therapeutic benefit of heat therapy may occur at temperatures above 40° C. because temperatures higher than 40° C. result in the recruitment of more thermoreceptors, thus leading to the desensitization of more heat activated and pain-associated receptors, such as TRPV1. Accordingly, current heat therapies operating at less than 40° C. are providing at best sub-optimal pain relief by failing to recruit certain thermoreceptors.
The present technology provides systems and methods for applying heat on the skin at temperatures above at least 40° C., and ranging up to 49° C. By providing such heat, skin temperature may at least temporarily rise above 40° C., thereby activating certain thermoreceptors. Therefore, the systems and methods described herein can provide effective pain relief by recruiting and desensitizing thermoreceptors such as TRPV1 and/or TRPM8.
The present technology includes methods of applying stimuli to reduce pain. For example, certain methods described herein activate the skin's thermoreceptors (e.g., the thermoTRPs) to block and/or otherwise mask the sensation of pain. In some embodiments, the present technology is configured to desensitize specific thermoreceptors such as TRPV1, TRPV2, TRPV3, TRPV4, TRPA1, and/or TRPM8 to reduce the sensation of pain.
In some embodiments, both cold and warm thermoreceptors are targeted. In other embodiments, only cold receptors or only warm receptors are targeted. The present technology and methods may be advantageous over existing pain relief pharmaceutical formulations or devices because they locally target pain producing regions of the body and do not contain risks inherent with chronic pharmaceutical dosing. Moreover, the present technology and methods may be advantageous over existing thermal therapies because the present technology may recruit and desensitize more thermoreceptors, thus providing a more effective therapy.
The present technology includes applying a stimulus to the skin of a patient. A number of different stimuli may utilized. For example, heat may be applied at any temperature in the range of about 35-49° C. For example, heat may be applied at about 35° C., 36° C., 37° C., 38° C., 39° C., 40° C., 41° C., 42° C., 43° C., 44° C., 45° C., 46° C., 47° C., 48° C., and/or 49° C. As discussed above, both cold and warm receptors (e.g., TRPM8 and/or TRPV1) may be activated by such temperatures, thereby desensitizing the receptors and contributing to pain reduction. Other suitable stimuli include compounds configured to activate cold receptors, warm receptors, and/or both cold and warm receptors. Such compounds may include, for example, menthol, menthol derivatives, icilin, capsaicin, and capsaicin derivatives.
In some embodiments, the stimulus is applied to one or more continuous surface areas of skin. For example, the stimulus may be applied to at least one surface area of skin that is 10 square inches or less, the stimulus may be applied to at least one surface area of skin that is less than about 6 square inches, the stimulus may be applied to at least one surface area of skin that is less than about 3 square inches, and/or the stimulus may be applied to at least one surface area of skin that is less than about 2 square inches. In other embodiments, the stimulus may be applied to a surface area of skin greater than 10 square inches.
In some embodiments, the stimulus delivery systems described herein can be used to apply the therapeutic stimuli to a patient. The stimulus delivery systems may apply the stimuli in many different patterns, magnitudes, cycles, etc. For example, a control unit (e.g., the control station 230) can be used to activate and control one or more wearable devices (e.g., the stimulus pods 110) to apply stimuli according to a predetermined heating cycle and/or pattern. In some embodiments, the stimulus pods 110 are configured to be placed in various locations on the skin of the patient to provide therapeutic heat treatment for relieving pain. The following disclosure details a few specific methods of applying stimuli using the delivery systems of the present technology. However, one skilled in the art will appreciate that the present technology can be used in many different manners to alleviate pain, treat ailments, etc., without deviating from the scope of the present technology. Moreover, while reference is made herein to the stimulus pod system 100, one skilled in the art will appreciate that the following methods can be carried out using other suitable heat producing devices and/or topical compounds—for example, those described in detail in U.S. Pat. No. 7,871,427, tilted “APPARATUS AND METHOD FOR USING A PORTABLE THERMAL DEVICE TO REDUCE ACCOMMODATION OF NERVE RECEPTORS,” and filed Feb. 8, 2006; and U.S. Pat. No. 8,579,953, titled “DEVICES AND METHODS FOR THERAPEUTIC HEAT TREATMENT,” and filed Dec. 8, 2008, each of which is incorporated herein by reference in its entirety.
1. Selected Embodiments of Low-Level Heating and Cooling Combined with Intermittent High-Level Heating
In some embodiments, the present technology can be configured to apply a continuous amount of low-level heat combined with discrete amounts or intermittent bursts of high-level heat to a patient. The intermittent bursts of high-level heat may enable recruitment, activation, and/or desensitization of thermoreceptors that are normally only activated at temperatures higher than those provided by traditional heat therapy. For example, as discussed above, tissue damage may occur following prolonged exposure to temperatures above 40° C. Accordingly, traditional heat therapies typically do not exceed 40° C. However, the present technology can apply heat therapy at temperatures above 40° C. because the present technology can be configured to apply intermittent bursts of heat above 40° C. while avoiding the prolonged exposure that may lead to tissue damage. Because heat can be applied at temperatures above 40° C., more thermoreceptors may be recruited, activated, and/or desensitized than in traditional static heat therapy.
As described in detail below, the bursts of heat can be at distinct locations within or around the areas producing the low-level heat. The low-level heat can be maintained as a constant application of heat (e.g., heating below 42° C., 41° C., 40° C., etc.) while the high-level heat is applied in intermittent bursts (e.g., milliseconds in some embodiments). In certain embodiments of the present disclosure, bursts of heat in the range of about 40-55° C. are applied to discrete areas of skin to excite the receptors. Other suitable ranges may include, for example, about 40-49° C., 40-48° C., 40-47° C., 40-46° C., and/or 40-45° C. In other embodiments, however, the thermal bursts can include temperatures higher or lower than the range of 40-55° C. For the purposes of this disclosure, thermal bursts can be defined as the application of increased heat in discrete areas where the temperature of the burst ranges from 0.1° C. to 25° C. or more above the baseline temperature of the continuous low-level heat application. The thermal bursts can include a ramp up speed ranging from milliseconds to minutes to reach a maximum temperature. In addition, and as described below, the size of the area applying the thermal burst may be relatively small in comparison to the area applying the low-level heat. In other embodiments, however, the area applying the thermal burst may be approximately equal to or less than the area applying the low-level heat.
In some embodiments, a method of applying heat to a living body includes applying a constant amount of heat to a region of the body at a first temperature (e.g., via a stimulus pod 110). The method can also include applying intermittent amounts of heat to the region (e.g., via the stimulus pod 110). The intermittent amounts of heat may be applied at a second temperature greater than the first temperature.
In some embodiments, a method of applying heat to a living body includes applying a constant amount of heat to a first region of the body at a first temperature (e.g., via a first one of the stimulus pods 110). The method can also include applying intermittent amounts of heat to a second region of the body (e.g., via a second one of the stimulus pods 110). The intermittent amounts of heat may be applied at a second temperature greater than the first temperature. In some embodiments, the second region can partially or fully overlap the first region. And in some embodiments, the intermittent amounts of heat are delivered at pre-selected, focused points wherein the surface area of the second region is smaller than the surface area of the first region.
A method configured in accordance with another embodiment of the disclosure includes a method of exciting thermoreceptors in a living organism. The method includes heating a first portion of skin with a generally constant amount of heat at a baseline temperature (e.g., via a first one of the stimulus pods 110), and heating a second portion of skin with a burst of heat at a temperature above the baseline temperature (e.g., via second one of the stimulus pods 110) while heating the first portion of skin with the generally constant amount of heat.
As described herein, certain methods in accordance with the present technology may utilize the stimulus pods 110.
The combination of the continuous low-level heating and intermittent high-level heating at discrete, focused regions provides several advantages over conventional heating systems. The augmentation of the continuous heating (or cooling), for example, provides enhanced pain relief by promoting blood flow, increasing flexibility, and relaxing muscles, ligaments, and other tissues. The illustrated configuration achieves enhanced pain relief by providing a strong stimulation of the thermoreceptors in the skin and subcutaneous tissues of the body by rapidly changing temperatures. Both the rapid change in temperature (e.g., the rapid increase in temperature during the intermittent burst) and the ability to stimulate at higher temperatures (e.g., above about 40° C.) recruits more thermoreceptors, including TRPV1 and/or TRPM8. Accordingly, the intermittent focused bursts of heat, combined with the constant heat, provide for better receptor recruitment and stimulation, thereby leading to increased desensitization, resulting in better analgesic results.
2. Selected Embodiments of Heat Cycling to Desensitize Thermoreceptors
In some embodiments, the present technology can be used to provide energy and/or heat to a patient to desensitize certain pain-associated thermoreceptors (e.g., TRPV1). The method includes increasing the temperature of a heating element (e.g., one or more of the stimulus surfaces 150 of the stimulus pods 110) to provide a first temperature ramp-up period, holding the temperature of the heating element at a predetermined therapeutic level, decreasing the temperature of the heating device during a ramp-down period, and holding the temperature of the heating device at a predetermined soak level, wherein the soak level temperature is less than the therapeutic level temperature by at least 1° C.
In operation, the heating device (e.g., one or more of the stimulus pods 110) may deliver heat intermittently. The heat may be applied for a period long enough to heat the skin to a desired level; upon reaching the desired skin temperature the device turns off and the skin is allowed to cool; after a preprogrammed interval the device may reactivate the heat unit and the cycle repeats. Alternatively, multiple cycles may be delivered sequentially for a predetermined duration.
In some embodiments, the ramp-up phases 1402, 1410, and 1502 may be less than about 4 seconds. For example, the ramp-up phase may be about 3 seconds, about 2 seconds, about 1 second, or less than 1 second. A short ramp up phase can be beneficial because a quick change in temperature (e.g., a short ramp-up phase) can recruit more thermoreceptors then a slow change in temperature. More specifically, a quick change in temperature can result in a rapid energy transfer between the heating device and the skin. This rapid energy transfer between the heating device and skin can activate thermoreceptors that may only traditionally be activated at higher static temperatures. Thus, more receptors may be recruited by “shocking” the receptors with a quick energy change. In contrast, a slower change in temperature (e.g., a ramp-up phase of about 4 seconds or more) provides a less intense change in energy and/or transfer of energy between the heating device and the skin and thus may not provide the same level of thermoreceptor recruitment. Accordingly, one benefit of the present technology is the recruitment of additional thermoreceptors by having a rapid energy transfer between the heating device and skin.
In some embodiments, the therapeutic temperature hold phase 1404 and the peak-time hold phase 1504 may be less than about 15 seconds. For example, the hold phases 1404 and 1504 may be about 1 second, about 2 seconds, about 3 seconds, about 4 seconds, about 5 seconds, about 6 seconds, about 7 seconds, about 8 seconds, about 9 seconds, about 10 seconds, about 11 seconds, about 12 seconds, about 13 seconds, about 14 seconds, or about 15 seconds. The temperature during hold phases 1404 and 1504 may be greater than about 40° C. For example, the temperature during hold phases 1404 and 1504 may be defined within a range, such as between 40-49° C., 40-48° C., 40-47° C., 40-46° C., or 40-45° C., 41-45° C., 42-45° C., 43-45° C., 44-45° C., or any other suitable range between an upper bound of about 49° C. and a lower bound of about 40° C. The temperature during hold phases 1404 and 1504 may also be defined as a specific temperature, such as about 40° C., 41° C., 42° C., 43° C., 44° C., 45° C., 46° C., 47° C., 48° C., or 49° C. Additionally or alternatively, the temperature during the hold phases 1404 and 1405 by be defined as a target skin temperature for a region of skin adjacent to the heating device. For example, the target skin temperature may be about 40° C., 41° C., 42° C., 43° C., 44° C., 45° C., 46° C., 47° C., 48° C., or 49° C. The target skin temperature may also be defined as a range of temperatures between, for example, 40-49° C., 40-48° C., 40-47° C., 40-46° C., or 40-45° C., 41-45° C., 42-45° C., 43-45° C., 44-45° C. In some embodiments, the temperature may alternatively be defined as an energy applied to the skin.
The ramp-down phase 1406 and the release phase 1506 may take several different forms. For example, the ramp-down phase may be actively controlled and take a linear form, such as illustrated by ramp-down phase 1406. The ramp-down phase may also simply be the result of turning off the energy or heat producing element such that a non-linear decay of heat occurs. For example, release phase 1506 illustrates one such example of the non-linear decay of heat. The decay time will depend on a number of factors, including peak temperature, soak temperature, and the thermal conductivity of the heating surface.
In some embodiments, the soak phase 1408 and 1508 may be held at a temperature higher than the basal body temperature of the user, thus allowing continued therapeutic effects by improving the blood flow to the region and providing muscle relaxation. In other embodiments, the heating device may simply be turned off during the soak phase 1408 and 1508, such that the temperature of the heating device is near the room temperature and/or the basal body temperature of the user (assuming complete decay). The duration of the soak phase 1408 and 1508 can be selected to maintain desensitization of previously desensitized thermoreceptors while simultaneously keeping a thermal flux value within the skin below a tissue-damage inducing threshold. For example, the soak time may be optimized based on identifying a duration for a thermoreceptor to reset (e.g., recover from the CA2+ influx and be capable of firing again). In some embodiments, for example, the soak time could be 60 seconds or less, such as about 55 seconds, about 50 seconds, about 45 seconds, about 40 seconds, about 35 seconds, about 30 seconds, about 25 seconds, about 20 seconds, about 15 seconds, about 10 seconds, or about 5 seconds. In some embodiments, the soak time may be greater than 60 seconds or less than 5 seconds.
The heating cycle including the ramp-up phase, the hold phase, the ramp-down phase, and the soak phase may be repeated at a frequency to maintain at least a partial desensitization of certain thermoreceptors (e.g., TRPV1). Moreover, the heating cycle may be repeated continuously for a preset duration (e.g., five minutes) or number of cycles (e.g., 100 cycles). In some embodiments, the heating cycle may continue until turned off.
The heating cycles described herein have several advantages over previous heat-based therapies. One benefit of certain embodiments of the present technology is the ability to minimize the total amount of heat and/or energy applied to the skin. As previously discussed, pulsing high levels of heat and/or energy with a ramp-up phase of about 4 seconds or less results in less total heat and/or total energy being applied to the skin but is nonetheless effective at recruiting thermoreceptors. For example, a short ramp-up phase (e.g., about 4 seconds or less) recruits more thermoreceptors than a long ramp-up phase. Thus, less total energy must be applied by relying in part on the rapid change of energy to recruit receptors, rather than relying on a total peak energy or temperature. Moreover, by pulsing energy, the benefit of this rapid change of energy may be repeatedly captured through repetitive ramp-up, hold, ramp-down, and soak cycles.
Another advantage of pulsing heat and/or energy is that less total heat and/or energy is applied to the skin through repeated heating cycles, since, during the soak cycles, the heat and/or energy applied to the skin can be minimal. This enables the hold phase of the heat cycle to have higher temperatures than traditional heating therapies, thereby recruiting more thermoreceptors. Accordingly, the heating cycles described herein enable maximal recruitment of thermoreceptors (and therapeutic efficacy) while the tissue remains at a temperature and/or thermal flux below a dangerous level.
Yet another advantage of the variable heat cycles is reduced power demand and consumption during the ramp-down or release phase when the thermal device does not draw power from the power supply, or draws reduced power from the power supply. Reduced power consumption results in a more efficient device with a longer life cycle and provides cost savings.
Yet another advantage of the present technology is that the heating devices can be portable and can be conveniently worn by the subject such that pain relief is available as needed. Moreover, in some embodiments, the user may selectively control certain parameters of the heating cycles via a control station such as a cell phone or other device capable of communicating with the stimulus producing device. For example, the user may be able to select, via a touch-screen display or other interactive portion of the control station (e.g., buttons, switches, etc.) a duration and/or pulse frequency for the heat cycling. The user may also select a baseline temperature to maintain during the soak phase and/or a maximum temperature not to surpass during the hold phase. The user can further select the number of heating cycles and/or total duration to apply the heating cycles.
According to aspects of the present technology, the heating devices and heating cycles described herein are designed to relieve pain and/or assist with healing in a variety of medical conditions such as low, mid, or upper back pain, muscular pain, dysmenorrhea, headaches, fibromyalgia, post-herpetic neuralgia, nerve injuries and neuropathies, injuries to extremities, and sprains and strains. The present technology may further be used in conjunction with other therapies known in the art, such as TENS. When combined with other therapies, the present technology may increase the efficacy of these other therapies.
3. Select Embodiments Including Non-Thermic Stimuli
Some embodiments of the present technology utilize topical non-thermal stimuli (e.g., topical compounds) to recruit, activate, and desensitize certain thermoreceptors. For example, menthol, icilin, menthol derivatives, capsaicin, capsaicin derivatives, cannabinoids, NSAIDs, paracetamol, paracetamol metabolites, and/or other compounds or formulations configured to stimulate thermoreceptors may be applied to the skin of a patient (collectively referred to as “non-thermal stimuli”). These non-thermal stimuli may be provided alone or in combination with each other, as well as with other heat therapies described herein. In one embodiment, for example, both capsaicin and menthol are applied to the skin to ensure recruitment of both TRPV1 and TRPM8. In such embodiments, capsaicin and menthol can be applied at the same time or at separate times via alternating applications. In some embodiments, however, menthol is exclusively applied, and/or capsaicin is exclusively applied. As discussed above, menthol and capsaicin may both induce cross-desensitization of TRPV1 and TRPM8. Therefore, even if menthol or capsaicin is exclusively applied, both TRPV1 and TRPM8 may both be recruited and desensitized.
The non-thermal stimuli may be applied to a surface area of the skin. As it is absorbed into the skin, the non-thermal stimuli may activate thermoreceptors. After excessive CA2+ influx, the thermoreceptors will desensitize, resulting in pain relief. In some embodiments, the surface are the non-thermal stimuli is applied to is 10 square inches or less. For example, the surface area may less than about 6 square inches, less than about 3 square inches, or less than about 2 square inches.
The non-thermal stimuli can be applied in a controlled manner similar to the heat cycling described above with respect to thermal stimuli. In some embodiments, the stimulus pods 110 described herein may be configured to apply the non-thermal stimuli (e.g., via the adhesive surface of the anchor 120 or via another applicator included on the stimulus pods 110). In some embodiments, however, the non-thermal stimuli may be applied via another device or mechanism known in the art. Regardless of the applicating device, certain embodiments of the present technology utilize repeatedly applying the non-thermal stimuli via controlled release. The controlled release will minimize unnecessary skin exposure to these non-thermal stimuli. Exemplary controlled release mechanisms include, for example, use of a time release chemical formula or fluidic wicking. Further controlled release mechanisms include electronically controlled release by microfluidics, a solenoid applicator, a micro-needle applicator, electrophoresis, magnetophoresis, and other techniques known in the art. The non-thermal stimuli may be repeatedly applied in a manner configured to stimulate and/or desensitize at least a subset of thermoreceptors.
In some embodiments, the non-thermal stimuli may be applied with the heat therapies described above. For example, a predetermined dose of non-thermal stimuli can be applied before (e.g., 5 minutes before, 1 minute before, immediately before) the initiation of a heat cycle. As another example, a predetermined dose of the non-thermal stimuli can be applied during the heating cycle and/or after the heating cycle. Applying heat may increase the efficacy of the non-thermal stimuli by, for example, increasing absorption and/or rate of absorption of the non-thermal stimuli. Accordingly, by combining the non-thermal stimuli with heat therapy, less overall non-thermal stimuli must be applied to achieve the same or greater therapeutic effect. Thus, in some embodiments, the predetermined dose may include a smaller overall dose or a less concentrated dose than doses applied without heat therapy.
When applied with heat, the non-thermal stimuli may be applied to the same surface area of skin as the heat, to a substantially similar surface area of skin as the heat, to an overlapping surface area of skin as the heat, or to a different area of skin as the heat. As can be appreciated by one of skill in the art, any number of overlapping and/or other patterns of application can be envisioned based on the disclosure herein and are included in the present technology.
The present technology may be better understood with reference to the following non-limiting examples.
1. A method of treating pain comprising pulsing heat into a volume of tissue including thermoreceptors, wherein—
2. The method of example 1, wherein pulsing heat into the volume of tissue comprises a heat cycle including a ramp-up phase, a hold phase, a ramp-down phase, and a soak phase.
3. The method of example 2, wherein the ramp-up phase is about 4 seconds or less.
4. The method of examples 2 or 3, wherein the hold phase is about 10 seconds or less.
5. The method of any one of examples 2-4, wherein the hold phase includes applying heat to the tissue at between 42 degrees and 49 degrees Celsius.
6. The method of any one of examples 2-5, wherein the soak phase includes applying heat at a basal body temperature or not applying heat.
7. The method of any one of examples 2-6, wherein the heat cycle is iteratively repeated for a set duration.
8. The method of examples 2-7, wherein the heat cycle is configured to desensitize at least a subset of the thermoreceptors.
9. The method of any one of examples 2-8, wherein the heat cycle is iteratively repeated at a frequency configured to induce desensitization of at least a subset of the thermoreceptors.
10. The method of any one of examples 2-8, further comprising iteratively repeating the heat cycle at a frequency configured to maintain desensitization of at least the subset of thermoreceptors.
11. The method of any one of examples 1-10, wherein the pulsed heat is configured to stimulate and/or induce desensitization of both warm thermoreceptors and cold thermoreceptors.
12. The method of any one of examples 1-11, wherein the pulsed heat is configured to stimulate and/or induce desensitization of TRPV1 receptors,
13. The method of any one of examples 1-11, wherein the pulsed heat is configured to stimulate and/or induce desensitization of TRPM8 receptors and/or TRPA1 receptors.
14. The method of any one of examples 1-11, wherein the pulsed heat is applied to a substantially continuous surface area of skin that is less than 3 square inches.
15. A method of treating pain comprising:
16. The method of example 15, wherein applying energy to the volume of tissue comprises a cycle including a ramp-up phase, a hold phase, a ramp-down phase, and a soak phase.
17. The method of example 16, wherein the ramp-up phase is about 4 seconds or less.
18. The method of example 16 or 17, wherein the hold phase is about 10 seconds or less, and wherein, during the hold phase, energy is applied to the volume of tissue to induce the skin temperature between 42 degrees and 49 degrees Celsius.
19. The method of any one of examples 16-18, wherein the soak phase comprises applying no energy to the volume of tissue, and wherein, during the soak phase, the temperature of the skin falls below 42 degrees Celsius.
20. The method of any one of examples 16-19, wherein the cycle is iteratively repeated for a set duration.
21. The method of any one of examples 16-19, wherein the cycle is configured to desensitize at least a subset of the thermoreceptors.
22. The method of any one of examples 16-21, wherein the cycle is iteratively repeated at a frequency configured to induce desensitization of at least a subset of the thermoreceptors.
23. The method of any one of examples 16-22, further comprising iteratively repeating the cycle at a frequency configured to maintain desensitization of at least the subset of thermoreceptors.
24. The method of any one of examples 15-23, wherein the energy is configured to stimulate and/or induce desensitization of both warm thermoreceptors and cold thermoreceptors.
25. The method of any one of examples 15-24, wherein the pulsed heat is configured to stimulate and/or induce desensitization of TRPV1 receptors.
26. The method of any one of examples 15-25, wherein the pulsed heat is configured to stimulate and/or induce desensitization of TRPM8 and/or TRPMA1 receptors.
27. A method of treating pain comprising:
28. The method of example 27, wherein repeatedly applying the topical compound comprises applying the topical compound two or more times within a therapy session.
29. The method of examples 27 or 28, wherein the topical compound is controllably applied via chemical time release or fluidic wicking.
30. The method of examples 27 or 28, wherein the topical compounds is controllably applied via electronically controlled microfluidics, electronically controlled electrophoresis, electronically controlled solenoid, electronically controlled micro-needle and/or electronically controlled magnetophoresis.
31. The method of any one of examples 27-30, wherein the topical compound is capsaicin, a capsaicin derivate, menthol, a menthol derivative, icilin, a cannabinoid, an NSAID, paracetamol, or paracetamol metabolites.
32. The method of any one of examples 27-31, wherein repeatedly applying a topical compound to a volume of tissue comprises alternatingly applying capsaicin or a capsaicin derivative and menthol, a menthol derivative, icilin, a cannabinoid, an NSAID, paracetamol, or paracetamol metabolites.
33. The method of any one of examples 27-32, further comprising applying heat to the volume of tissue concurrent with the topical compound to increase the absorption of the topical compound.
34. The method of any one of examples 27-33, wherein the topical compound is configured to induce desensitization of both warm thermoreceptors and cold thermoreceptors.
35. The method of any one of examples 27-34, wherein the topical compound is configured to induce desensitization of TRPV1.
36. The method of any one of examples 27-35, wherein the topical compound is configured to induce desensitization of TRPM8 and/or TRPA1.
37. A system for treating pain, the system comprising:
38. The system of example 37, further comprising an electrical circuit configured to monitor the temperature of the skin to ensure that the pulsed energy does not cause an injury to the skin.
39. The system of example 38, wherein the electrical circuit is configured to utilize a look-up table, a formula, a chart, or other source of information to predict the characteristic of thermal energy that causes injury to the skin.
40. The system of any one of examples 37-39, further comprising a temperature measuring element configured to sense the temperature of the skin.
41. The system of any one of examples 38-40, wherein the electrical circuit is configured to transmit monitored characteristics to a control device.
42. The system of example 41, wherein the monitored characteristics include the skin's thermal transfer capacity and/or the skin's blood flow.
43. The system of any one of examples 37-42, wherein the pulsed energy is configured to induce a skin temperature between 42 degrees and 49 degrees Celsius.
44. The system of any one of examples 37-43, wherein the pulsed energy is configured to desensitize at least a subset of the thermoreceptors.
45. A method of pulsing heat between 42° C. to 49° C. and applying the pulsed heat to a small surface area of skin thereby activating underlying warm thermoreceptors, and cold thermoreceptors in the skin to produce relief from acute, sub-acute, and chronic pain.
46. The method of example 45, wherein applying the pulsed heat to the skin provides a thermal flux that does not cause tissue injury.
46. The method of example 45, wherein applying the pulsed heat keeps phasic thermoreceptors shutdown for prolonged periods.
47. The method of example 45, wherein the small surface area is between 0.5 to 3 square inches and wherein applying the heat to the small surface area minimizes the amount of thermal energy delivered to the skin.
48. The method of example 45, wherein applying the pulsed heat to the skin comprises applying a therapeutic dose of heat, wherein the therapeutic dose of heat is generated by a conductive heating element controlled by a microprocessor.
49. The method of example 45 wherein the pulsed heat is produced by an electrically resistive heating element with very low thermal mass to facilitate fast thermal rise on activation and minimal retained heat when turned off.
50. The method of example 45 wherein the pulsed heat comprises a therapeutic dose of heat delivered to the skin and wherein applying the pulsed heat comprises applying the therapeutic dose of heat using a radiation-heating element controlled by a microprocessor.
51. The method of example 45 wherein the pulsed heat comprises a therapeutic dose of heat delivered to the skin and wherein applying the pulsed heat comprises applying the therapeutic dose of heat using a convective heating element controlled by a microprocessor.
52. The method of example 45 wherein the pulsed heat can be a saw-tooth and or pulsed wave.
53. The method of example 45 wherein heat flux produced by a heating element is controlled such that the skin temperature is raised over a series of temperature steps prior to a final temperature.
54. An electrical circuit configured to monitor the temperature of skin to ensure that a heating element in contact with the skin and configured to deliver pulses of heat does not cause a thermal injury to the skin.
55. The electrical circuit of example 54, wherein the electrical circuit is configured to utilize a look-up table, a formula, a chart, or other sources of information to predict the characteristic of thermal energy that causes thermal injury to the skin.
56. The electrical circuit of example 54, further comprising a temperature measuring element configured to monitor the temperature of the skin, wherein the temperature measuring element is located at the center of the heating element.
57. The electrical circuit of example 54, wherein monitoring the temperature of skin comprises monitoring the temperature using a non-contact method of measuring skin temperature.
58. The electrical circuit of example 54, wherein the electrical circuit is configured to provide protection and warning against a malfunctioning internal power source or battery.
59. The electrical circuit of example 54, wherein the electrical circuit is configured to transmit information about characteristics of the skin to a mobile app associated with the electrical circuit.
60. The electrical circuit of example 59, wherein the transmitted information comprises information about the skin's thermal transfer capacity.
61. The electrical circuit of example 59, wherein the transmitted information comprises information about the skin's blood flow.
62. A method of stimulating cold fibers to activate these fibers to produce analgesia and a hedonistic experience through thermal stimulation in order to provide both pain relief and a sense of relaxation and empathy.
63. The method of example 62, wherein stimulating cold fibers is used to treat headaches, muscular pain, pain in joints, pain from nerve injury irritation or compression, back, neck, and musculoskeletal pain.
64. A method of exposing skin to cold temperatures for repeated and short durations of time.
65. A method of pulsing heat from water sources to provide pain relief, comprising: applying intense but short pulses of heated water to skin in order to activate both A-Δ and A-β receptors.
66. A method of applying or exposing topical compounds for repeated, short durations to a surface area of skin to desensitize receptors and produce relief from acute, sub-acute and chronic pain.
67. The method of example 66 wherein the surface area of skin exposed is 0.5 to 3 square inches.
68. The method of example 66 wherein the compound's application to the skin is controlled by chemical time release.
69. The method of example 66 wherein the compound's application to the skin is controlled by fluidic wicking.
70. The method of example 66 wherein the compound's application to the skin is by electronically controlled microfluidics.
71. The method of example 66 wherein the compound's application to the skin is by electronically controlled electrophoresis.
72. The method of example 66 wherein the compound's application to the skin is by magnetophoresis or electronically controlled magnetophoresis.
73. The method of example 66 wherein the compound's application to the skin is by electronically controlled solenoid.
74. The method of example 66 wherein the compound's application to the skin is by electronically controlled micro-needles.
75. The method of example 66 wherein the topical compound is capsaicin.
76. The method of example 66, further comprising alternating the application or exposure of Capsaicin and Menthol to the skin to produce relief from acute, sub-acute, and chronic pain.
77. The method of example 66, further comprising applying capsaicin to one skin area and menthol to another skin area to produce relief from acute, sub-acute, and chronic pain.
78. A method of applying heat on the skin to improve the absorption of topical compound/s.
79. The method of example 78, wherein the heat is pulsed.
80. A system for treating pain, the system comprising:
81. The system of example 80, wherein the pulsed energy includes a ramp-up phase, a hold phase, a ramp-down phase, and a soak phase.
82. The system of example 81, wherein during the hold phase, the energy producing element applies directs and energy at the volume of tissue configured to induce a skin temperature between 42 and 49 degrees Celsius.
83. The system of any one of examples 80-82, wherein the topical compound is capsaicin, a capsaicin derivate, menthol, a menthol derivative, icilin, a cannabinoid, an NSAID, paracetamol, or a paracetamol metabolite.
84. The system of any one of examples 80-83, wherein the topical compound is controllably applied via chemical time release or fluidic wicking
85. The system of any one of examples 80-83, wherein the topical compound is controllably applied via electronically controlled microfluidics, electronically controlled electrophoresis, electronically controlled solenoid, magnetophoresis and/or electronically controlled magnetophoresis.
86. The system of any one of examples 80-85, wherein the pulsed energy and/or the topical compound are configured to stimulate and desensitize TRPV1, TRPM8, and/or TRPA1.
Unless the context clearly requires otherwise, throughout the description and the claims, the words “comprise,” “comprising,” and the like are to be construed in an inclusive sense, as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to.” As used herein, the terms “connected,” “coupled,” or any variant thereof, means any connection or coupling, either direct or indirect, between two or more elements; the coupling of connection between the elements can be physical, logical, or a combination thereof. Additionally, the words “herein,” “above,” “below,” and words of similar import, when used in this application, shall refer to this application as a whole and not to any particular portions of this application. Where the context permits, words in the above Detailed Description using the singular or plural number may also include the plural or singular number respectively. The word “or,” in reference to a list of two or more items, covers all of the following interpretations of the word: any of the items in the list, all of the items in the list, and any combination of the items in the list.
The above detailed description of embodiments of the present technology is not intended to be exhaustive or to limit the present technology to the precise form disclosed above. While specific embodiments of, and examples for, the present technology are described above for illustrative purposes, various equivalent modifications are possible within the scope of the present technology, as those skilled in the relevant art will recognize. The teachings of the present technology provided herein can be applied to other systems, not necessarily the system described above. The elements and acts of the various embodiments described above can be combined to provide further embodiments. All of the above patents and applications and other references, including any that may be listed in accompanying filing papers, are incorporated herein by reference. Aspects of the present technology can be modified, if necessary, to employ the systems, functions, and concepts of the various references described above to provide yet further embodiments of the present technology.
These and other changes can be made to the present technology in light of the above Detailed Description. While the above description details certain embodiments of the present technology and describes the best mode contemplated, no matter how detailed the above appears in text, the present technology can be practiced in many ways. Details of the system may vary considerably in its implementation details, while still being encompassed by the present technology disclosed herein. As noted above, particular terminology used when describing certain features or aspects of the present technology should not be taken to imply that the terminology is being redefined herein to be restricted to any specific characteristics, features, or aspects of the present technology with which that terminology is associated. In general, the terms used in the following claims should not be construed to limit the present technology to the specific embodiments disclosed in the specification, unless the above Detailed Description section explicitly defines such terms. Accordingly, the actual scope of the present technology encompasses not only the disclosed embodiments, but also all equivalent ways of practicing or implementing the present technology.
The present application claims priority to U.S. Provisional Patent Application No. 62/639,930, titled “SYSTEMS AND METHODS FOR IMPROVED PAIN RELIEF FROM ACTIVATION OF THERMAL COLD FIBERS,” filed Mar. 7, 2018, the disclosure of which is hereby incorporated by reference in its entirety.
| Filing Document | Filing Date | Country | Kind |
|---|---|---|---|
| PCT/US2019/021203 | 3/7/2019 | WO |
| Publishing Document | Publishing Date | Country | Kind |
|---|---|---|---|
| WO2019/173623 | 9/12/2019 | WO | A |
| Number | Name | Date | Kind |
|---|---|---|---|
| 1377158 | Radisson | May 1921 | A |
| 3841306 | Hallgren | Oct 1974 | A |
| 3857397 | Brosseau | Dec 1974 | A |
| 4107509 | Scher et al. | Aug 1978 | A |
| 4201218 | Feldman et al. | May 1980 | A |
| 4245149 | Fairlie | Jan 1981 | A |
| 4279255 | Hoffman | Jul 1981 | A |
| 4303074 | Bender | Dec 1981 | A |
| 4310745 | Bender | Jan 1982 | A |
| 4348584 | Gale et al. | Sep 1982 | A |
| 4396011 | Mack et al. | Aug 1983 | A |
| 4398535 | Guibert | Aug 1983 | A |
| 4487603 | Harris | Dec 1984 | A |
| 4518851 | Oppitz | May 1985 | A |
| 4570640 | Barsa | Feb 1986 | A |
| 4575097 | Brannigan et al. | Mar 1986 | A |
| 4585002 | Kissin | Apr 1986 | A |
| 4608985 | Crish | Sep 1986 | A |
| 4719919 | Marchosky | Jan 1988 | A |
| 4736088 | Bart | Apr 1988 | A |
| 4817628 | Zea lear | Apr 1989 | A |
| 4889526 | Rauscher | Dec 1989 | A |
| 4930317 | Klein | Jun 1990 | A |
| 4939149 | Blumberg | Jul 1990 | A |
| 5031618 | Mullett | Jul 1991 | A |
| 5035891 | Runkel | Jul 1991 | A |
| 5057104 | Chess | Oct 1991 | A |
| 5061234 | Chaney | Oct 1991 | A |
| 5092835 | Schurig | Mar 1992 | A |
| 5097828 | Deutsch | Mar 1992 | A |
| 5138138 | Theilacker et al. | Aug 1992 | A |
| 5188104 | Vvernicke | Feb 1993 | A |
| 5192527 | Abrahmsohn | Mar 1993 | A |
| 5215089 | Baker, Jr. | Jun 1993 | A |
| 5224927 | Tapper | Jul 1993 | A |
| 5224928 | Sibalis | Jul 1993 | A |
| 5231988 | Wernicke | Aug 1993 | A |
| 5251634 | Weinberg | Oct 1993 | A |
| 5330515 | Rutecki | Jul 1994 | A |
| 5335657 | Terry, Jr. | Aug 1994 | A |
| 5336255 | Kanare et al. | Aug 1994 | A |
| 5351394 | Weinberg | Oct 1994 | A |
| 5354320 | Schaldach | Oct 1994 | A |
| 5374284 | Guibert et al. | Dec 1994 | A |
| 5395398 | Rogozinski | Mar 1995 | A |
| 5423874 | D'Alerta | Jun 1995 | A |
| 5447530 | Guibert et al. | Sep 1995 | A |
| 5451747 | Sullivan et al. | Sep 1995 | A |
| 5458625 | Kendall | Oct 1995 | A |
| 5499967 | Teillaud | Mar 1996 | A |
| 5527797 | Eisenberg | Jun 1996 | A |
| 5531778 | Maschino | Jul 1996 | A |
| 5540730 | Terry, Jr. | Jul 1996 | A |
| 5558633 | Phipps | Sep 1996 | A |
| 5571150 | Wernicke | Nov 1996 | A |
| 5580350 | Guibert et al. | Dec 1996 | A |
| 5601618 | James | Feb 1997 | A |
| 5628769 | Saringer | May 1997 | A |
| 5658583 | Zhang et al. | Aug 1997 | A |
| 5683422 | Rise | Nov 1997 | A |
| 5707400 | Terry, Jr. | Jan 1998 | A |
| 5735889 | Burkett et al. | Apr 1998 | A |
| 5741318 | Ouellette et al. | Apr 1998 | A |
| 5755750 | Petruska | May 1998 | A |
| 5797898 | Santini, Jr. et al. | Aug 1998 | A |
| 5800481 | Loos | Sep 1998 | A |
| 5814019 | Steinbach | Sep 1998 | A |
| 5817139 | Kasano | Oct 1998 | A |
| 5817145 | Augustine et al. | Oct 1998 | A |
| 5830207 | Leeb | Nov 1998 | A |
| 5830208 | Muller | Nov 1998 | A |
| 5837005 | Viltro et al. | Nov 1998 | A |
| 5860945 | Cramer et al. | Jan 1999 | A |
| 5861022 | Hipskind | Jan 1999 | A |
| 5868743 | Saul | Feb 1999 | A |
| 5876422 | Van Groeningen | Mar 1999 | A |
| 5891189 | Payne, Jr. | Apr 1999 | A |
| 5893991 | Newell | Apr 1999 | A |
| 5906637 | Davis et al. | May 1999 | A |
| 5925072 | Cramer et al. | Jul 1999 | A |
| 5928195 | Malamud et al. | Jul 1999 | A |
| 5947914 | Augustine | Sep 1999 | A |
| 5954680 | Augustine | Sep 1999 | A |
| 5964721 | Augustine | Oct 1999 | A |
| 5964723 | Augustine | Oct 1999 | A |
| 5984995 | White | Nov 1999 | A |
| 5986163 | Augustine | Nov 1999 | A |
| 5993414 | Haller | Nov 1999 | A |
| 5997501 | Gross | Dec 1999 | A |
| 6010527 | Augustine et al. | Jan 2000 | A |
| 6012457 | Lesh | Jan 2000 | A |
| 6013097 | Augustine et al. | Jan 2000 | A |
| 6045518 | Augustine | Apr 2000 | A |
| 6058331 | King | May 2000 | A |
| 6066163 | John | May 2000 | A |
| 6066164 | Macher et al. | May 2000 | A |
| 6071254 | Augustine | Jun 2000 | A |
| 6095992 | Augustine | Aug 2000 | A |
| 6096067 | Cramer et al. | Aug 2000 | A |
| 6110197 | Augustine et al. | Aug 2000 | A |
| 6113561 | Augustine | Sep 2000 | A |
| 6146732 | Davis et al. | Nov 2000 | A |
| 6164283 | Lesh | Dec 2000 | A |
| 6185455 | Loeb | Feb 2001 | B1 |
| 6208894 | Schulman | Mar 2001 | B1 |
| 6213965 | Augustine et al. | Apr 2001 | B1 |
| 6213966 | Augustine | Apr 2001 | B1 |
| 6217535 | Augustine | Apr 2001 | B1 |
| 6235049 | Nazerian | May 2001 | B1 |
| 6238421 | Gunther et al. | May 2001 | B1 |
| 6241697 | Augustine | Jun 2001 | B1 |
| 6246912 | Sluijter | Jun 2001 | B1 |
| 6248084 | Augustine et al. | Jun 2001 | B1 |
| 6248126 | Lesser | Jun 2001 | B1 |
| 6254557 | Augustine et al. | Jul 2001 | B1 |
| 6264622 | Augustine | Jul 2001 | B1 |
| 6267740 | Augustine et al. | Jul 2001 | B1 |
| 6283931 | Augustine | Sep 2001 | B1 |
| 6293917 | Augustine et al. | Sep 2001 | B1 |
| 6314325 | Fitz | Nov 2001 | B1 |
| 6326020 | Kohane | Dec 2001 | B1 |
| 6331695 | West | Dec 2001 | B1 |
| 6353211 | Chen | Mar 2002 | B1 |
| 6364899 | Dobak, III | Apr 2002 | B1 |
| 6405732 | Edwards | Jun 2002 | B1 |
| 6406448 | Augustine | Jun 2002 | B1 |
| 6407307 | Augustine | Jun 2002 | B1 |
| 6416495 | Kriesel | Jul 2002 | B1 |
| 6419651 | Augustine | Jul 2002 | B1 |
| 6423018 | Augustine | Jul 2002 | B1 |
| 6436063 | Augustine et al. | Aug 2002 | B1 |
| 6453195 | Thompson | Sep 2002 | B1 |
| 6454759 | Krulevitch | Sep 2002 | B2 |
| 6464687 | Akira | Oct 2002 | B1 |
| 6465709 | Sun et al. | Oct 2002 | B1 |
| 6468295 | Augustine et al. | Oct 2002 | B2 |
| 6485506 | Augustine | Nov 2002 | B2 |
| 6527695 | Davey | Mar 2003 | B1 |
| 6528076 | Small | Mar 2003 | B2 |
| 6539250 | Bettinger | Mar 2003 | B1 |
| 6551235 | Forsell | Apr 2003 | B2 |
| 6554822 | Holschneider | Apr 2003 | B1 |
| 6567696 | Voznesensky et al. | May 2003 | B2 |
| 6571123 | Ives | May 2003 | B2 |
| 6571125 | Thompson | May 2003 | B2 |
| 6572871 | Church et al. | Jun 2003 | B1 |
| 6580012 | Augustine et al. | Jun 2003 | B1 |
| 6589271 | Tzeng | Jul 2003 | B1 |
| 6600956 | Maschino | Jul 2003 | B2 |
| 6605012 | Muller | Aug 2003 | B2 |
| 6610713 | Tracey | Aug 2003 | B2 |
| 6622048 | Mann | Sep 2003 | B1 |
| 6666845 | Hooper | Dec 2003 | B2 |
| 6669683 | Santini, Jr. et al. | Dec 2003 | B2 |
| 6684105 | Cohen | Jan 2004 | B2 |
| 6710313 | Asami et al. | Mar 2004 | B1 |
| 6716235 | Augustine et al. | Apr 2004 | B2 |
| 6720402 | Langer | Apr 2004 | B2 |
| 6745078 | Buchner | Jun 2004 | B1 |
| 6746474 | Saadat | Jun 2004 | B2 |
| 6755621 | Lopez | Jun 2004 | B2 |
| 6761715 | Carroll | Jul 2004 | B2 |
| 6764678 | Weber | Jul 2004 | B2 |
| 6770022 | Mechlenburg | Aug 2004 | B2 |
| 6796956 | Hartlaub et al. | Sep 2004 | B2 |
| 6802811 | Slepian | Oct 2004 | B1 |
| 6808522 | Richards | Oct 2004 | B2 |
| 6832114 | Whitehurst et al. | Dec 2004 | B1 |
| 6835184 | Sage | Dec 2004 | B1 |
| 6838471 | Tracey | Jan 2005 | B2 |
| 6840915 | Augustine | Jan 2005 | B2 |
| 6840955 | Ein | Jan 2005 | B2 |
| 6860852 | Schoenenberger | Mar 2005 | B2 |
| 6871092 | Piccone | Mar 2005 | B2 |
| 6871099 | Whitehurst et al. | Mar 2005 | B1 |
| 6885888 | Rezai | Apr 2005 | B2 |
| 6893453 | Agarwal et al. | May 2005 | B2 |
| 6921374 | Augustine | Jul 2005 | B2 |
| 6921413 | Mahadevan-Jansen | Jul 2005 | B2 |
| 6925317 | Samuels | Aug 2005 | B1 |
| 6928320 | King | Aug 2005 | B2 |
| 6941171 | Mann | Sep 2005 | B2 |
| 6976982 | Santini, Jr. et al. | Dec 2005 | B2 |
| 6978174 | Gelfand | Dec 2005 | B2 |
| 7016723 | Morris | Mar 2006 | B2 |
| 7022093 | Smith et al. | Apr 2006 | B2 |
| 7031768 | Anderson | Apr 2006 | B2 |
| 7033571 | Gutowska | Apr 2006 | B2 |
| 7072802 | Hartlaub | Jul 2006 | B2 |
| 7076307 | Boveja et al. | Jul 2006 | B2 |
| 7108680 | Rohr | Sep 2006 | B2 |
| 7113821 | Sun | Sep 2006 | B1 |
| 7155279 | Whitehurst et al. | Dec 2006 | B2 |
| 7155281 | Fayram | Dec 2006 | B1 |
| 7162303 | Levin et al. | Jan 2007 | B2 |
| 7167743 | Heruth | Jan 2007 | B2 |
| 7204832 | Altshuler | Apr 2007 | B2 |
| 7204833 | Osorio | Apr 2007 | B1 |
| 7209787 | DiLorenzo | Apr 2007 | B2 |
| 7209788 | Nicolelis et al. | Apr 2007 | B2 |
| 7226426 | Thomson | Jun 2007 | B2 |
| 7231254 | DiLorenzo | Jun 2007 | B2 |
| 7236822 | Dobak, III | Jun 2007 | B2 |
| 7242983 | Frei | Jul 2007 | B2 |
| 7244253 | Neev | Jul 2007 | B2 |
| 7263405 | Boveja et al. | Aug 2007 | B2 |
| 7277758 | DiLorenzo | Oct 2007 | B2 |
| 7286880 | Olson | Oct 2007 | B2 |
| 7315761 | De Ridder | Jan 2008 | B2 |
| 7319899 | Keizer | Jan 2008 | B2 |
| 7324851 | DiLorenzo | Jan 2008 | B1 |
| 7337005 | Kim | Feb 2008 | B2 |
| 7337006 | Kim | Feb 2008 | B2 |
| 7340304 | MacDonald | Mar 2008 | B2 |
| 7389145 | Kilgore | Jun 2008 | B2 |
| 7613515 | Knudson | Nov 2009 | B2 |
| 7634317 | Ben-David et al. | Dec 2009 | B2 |
| 7672714 | Kuo | Mar 2010 | B2 |
| 7783361 | Docherty et al. | Aug 2010 | B2 |
| 7871427 | Dunbar et al. | Jan 2011 | B2 |
| 8060208 | Kilgore | Nov 2011 | B2 |
| 8082039 | Kim et al. | Dec 2011 | B2 |
| 8160695 | Dacey, Jr. et al. | Apr 2012 | B2 |
| 8165668 | Dacey, Jr. et al. | Apr 2012 | B2 |
| 8165669 | Dacey, Jr. et al. | Apr 2012 | B2 |
| 8170658 | Dacey, Jr. et al. | May 2012 | B2 |
| 8170659 | Dacey, Jr. et al. | May 2012 | B2 |
| 8170660 | Dacey, Jr. et al. | May 2012 | B2 |
| 8180446 | Dacey, Jr. et al. | May 2012 | B2 |
| 8180447 | Dacey, Jr. et al. | May 2012 | B2 |
| 8195287 | Dacey, Jr. et al. | Jun 2012 | B2 |
| 8233976 | Dacey, Jr. et al. | Jul 2012 | B2 |
| 8244369 | Kreindel | Aug 2012 | B2 |
| 8391970 | Tracey | Mar 2013 | B2 |
| 8412338 | Faltys | Apr 2013 | B2 |
| 8579953 | Dunbar | Nov 2013 | B1 |
| 8630706 | Dacey, Jr. et al. | Jan 2014 | B2 |
| 8702775 | Dunbar et al. | Apr 2014 | B2 |
| 8989858 | Dacey, Jr. et al. | Mar 2015 | B2 |
| 9014802 | Dacey, Jr. et al. | Apr 2015 | B2 |
| 9020591 | Dacey, Jr. et al. | Apr 2015 | B2 |
| 9020592 | Dacey, Jr. et al. | Apr 2015 | B2 |
| 9358374 | Dacey, Jr. et al. | Jun 2016 | B2 |
| 9789315 | Dacey, Jr. et al. | Oct 2017 | B2 |
| 9937072 | Chabal et al. | Apr 2018 | B2 |
| 10092692 | Dacey, Jr. et al. | Oct 2018 | B2 |
| 10182937 | Smith | Jan 2019 | B2 |
| 10188547 | Dunbar et al. | Jan 2019 | B2 |
| 10603208 | Dunbar et al. | Mar 2020 | B2 |
| 20010037104 | Zhang et al. | Nov 2001 | A1 |
| 20020019652 | Da Silva et al. | Feb 2002 | A1 |
| 20020026226 | Ein | Feb 2002 | A1 |
| 20020038137 | Stein | Mar 2002 | A1 |
| 20020058972 | Minogue | May 2002 | A1 |
| 20020068964 | Dobak, III | Jun 2002 | A1 |
| 20020095134 | Pettis et al. | Jul 2002 | A1 |
| 20020173827 | Jones et al. | Nov 2002 | A1 |
| 20020183813 | Augustine et al. | Dec 2002 | A1 |
| 20030013998 | Augustine | Jan 2003 | A1 |
| 20030014097 | Putz et al. | Jan 2003 | A1 |
| 20030045914 | Cohen | Mar 2003 | A1 |
| 20030050677 | Gross | Mar 2003 | A1 |
| 20030060860 | Foster et al. | Mar 2003 | A1 |
| 20030069618 | Smith et al. | Apr 2003 | A1 |
| 20030097161 | Firlik et al. | May 2003 | A1 |
| 20030125648 | Leason et al. | Jul 2003 | A1 |
| 20030125661 | Yerushalmy | Jul 2003 | A1 |
| 20030176901 | May | Sep 2003 | A1 |
| 20030219470 | Zhang et al. | Nov 2003 | A1 |
| 20040013716 | Gale et al. | Jan 2004 | A1 |
| 20040049134 | Tosaya et al. | Mar 2004 | A1 |
| 20040073258 | Church et al. | Apr 2004 | A1 |
| 20040098065 | Hagglof et al. | May 2004 | A1 |
| 20040127886 | Daum | Jul 2004 | A1 |
| 20040172086 | Knudson | Sep 2004 | A1 |
| 20040176812 | Knudson | Sep 2004 | A1 |
| 20040181262 | Bauhahn | Sep 2004 | A1 |
| 20040211569 | Vinegar et al. | Oct 2004 | A1 |
| 20040220621 | Zhou et al. | Nov 2004 | A1 |
| 20050021103 | DiLorenzo | Jan 2005 | A1 |
| 20050021104 | DiLorenzo | Jan 2005 | A1 |
| 20050070974 | Knudson et al. | Mar 2005 | A1 |
| 20050075669 | King | Apr 2005 | A1 |
| 20050075701 | Shafer | Apr 2005 | A1 |
| 20050075702 | Shafer | Apr 2005 | A1 |
| 20050076908 | Lee et al. | Apr 2005 | A1 |
| 20050080463 | Stahmann et al. | Apr 2005 | A1 |
| 20050119713 | Whitehurst et al. | Jun 2005 | A1 |
| 20050125044 | Tracey | Jun 2005 | A1 |
| 20050137648 | Cosendai et al. | Jun 2005 | A1 |
| 20050138934 | Weigert et al. | Jun 2005 | A1 |
| 20050149123 | Lesser | Jul 2005 | A1 |
| 20050149148 | King | Jul 2005 | A1 |
| 20050203501 | Aldrich | Sep 2005 | A1 |
| 20050215947 | Heruth | Sep 2005 | A1 |
| 20050216072 | Mahadevan-Jansen | Sep 2005 | A1 |
| 20050234523 | Levin et al. | Oct 2005 | A1 |
| 20050240126 | Foley et al. | Oct 2005 | A1 |
| 20050256555 | Fisher et al. | Nov 2005 | A1 |
| 20050273029 | Harris et al. | Dec 2005 | A1 |
| 20050277912 | John | Dec 2005 | A1 |
| 20050278001 | Qin | Dec 2005 | A1 |
| 20050282906 | Tracey | Dec 2005 | A1 |
| 20050288730 | Deem | Dec 2005 | A1 |
| 20060004417 | Rossing | Jan 2006 | A1 |
| 20060036209 | Subramony | Feb 2006 | A1 |
| 20060058694 | Clark | Mar 2006 | A1 |
| 20060100668 | Ben-David et al. | May 2006 | A1 |
| 20060122454 | Riehl | Jun 2006 | A1 |
| 20060122663 | Mandell | Jun 2006 | A1 |
| 20060122675 | Libbus | Jun 2006 | A1 |
| 20060155348 | Decharms | Jul 2006 | A1 |
| 20060173493 | Armstrong | Aug 2006 | A1 |
| 20060178703 | Huston et al. | Aug 2006 | A1 |
| 20060190053 | Dobak, III | Aug 2006 | A1 |
| 20060195168 | Dunbar et al. | Aug 2006 | A1 |
| 20060247721 | Maschino | Nov 2006 | A1 |
| 20060247722 | Maschino | Nov 2006 | A1 |
| 20060247739 | Wahlstrand | Nov 2006 | A1 |
| 20060258962 | Kopanic et al. | Nov 2006 | A1 |
| 20060259077 | Pardo | Nov 2006 | A1 |
| 20060270944 | King | Nov 2006 | A1 |
| 20060282134 | Shapiro | Dec 2006 | A1 |
| 20060293721 | Tarver | Dec 2006 | A1 |
| 20070027484 | Guzman | Feb 2007 | A1 |
| 20070027496 | Parnis | Feb 2007 | A1 |
| 20070027497 | Parnis | Feb 2007 | A1 |
| 20070055316 | Godara | Mar 2007 | A1 |
| 20070060984 | Webb | Mar 2007 | A1 |
| 20070093870 | Maschino | Apr 2007 | A1 |
| 20070106339 | Errico et al. | May 2007 | A1 |
| 20070129760 | Demarais | Jun 2007 | A1 |
| 20070129774 | Bourget | Jun 2007 | A1 |
| 20070135875 | Demarais | Jun 2007 | A1 |
| 20070142875 | Shalev | Jun 2007 | A1 |
| 20070150025 | DiLorenzo et al. | Jun 2007 | A1 |
| 20070150029 | Bourget | Jun 2007 | A1 |
| 20070156032 | Gordon | Jul 2007 | A1 |
| 20070156206 | Wahlstrand | Jul 2007 | A1 |
| 20070167984 | Kieval | Jul 2007 | A1 |
| 20070173899 | Levin et al. | Jul 2007 | A1 |
| 20070179557 | Steven | Aug 2007 | A1 |
| 20070191906 | Iyer | Aug 2007 | A1 |
| 20070225781 | Saadat et al. | Sep 2007 | A1 |
| 20070233211 | Galer | Oct 2007 | A1 |
| 20070255374 | Kolafa | Nov 2007 | A1 |
| 20080045879 | Prausnitz | Feb 2008 | A1 |
| 20080077198 | Webb | Mar 2008 | A1 |
| 20080091248 | Libbus | Apr 2008 | A1 |
| 20080103567 | Augustine et al. | May 2008 | A1 |
| 20080249439 | Tracey | Oct 2008 | A1 |
| 20080300657 | Stultz | Dec 2008 | A1 |
| 20080312522 | Rowlandson et al. | Dec 2008 | A1 |
| 20090062896 | Overstreet | Mar 2009 | A1 |
| 20090131835 | Voorhees et al. | May 2009 | A1 |
| 20090149797 | Dacey, Jr. et al. | Jun 2009 | A1 |
| 20090149798 | Dacey, Jr. et al. | Jun 2009 | A1 |
| 20090149799 | Dacey, Jr. et al. | Jun 2009 | A1 |
| 20090187230 | Dilorenzo | Jul 2009 | A1 |
| 20090222072 | Robinson et al. | Sep 2009 | A1 |
| 20090275997 | Faltys et al. | Nov 2009 | A1 |
| 20090292237 | Overstreet | Nov 2009 | A1 |
| 20100036445 | Sakai et al. | Feb 2010 | A1 |
| 20100256720 | Overstreet | Oct 2010 | A1 |
| 20110021930 | Mazzeo et al. | Jan 2011 | A1 |
| 20110054569 | Zitnik | Mar 2011 | A1 |
| 20110106208 | Faltys et al. | May 2011 | A1 |
| 20110190849 | Faltys et al. | Aug 2011 | A1 |
| 20110279963 | Kumar et al. | Nov 2011 | A1 |
| 20120290035 | Levin et al. | Nov 2012 | A1 |
| 20130041331 | Overstreet | Feb 2013 | A1 |
| 20130079749 | Overstreet | Mar 2013 | A1 |
| 20130079834 | Levine | Mar 2013 | A1 |
| 20140088580 | Wittenberger et al. | Mar 2014 | A1 |
| 20140148756 | Yodfat et al. | May 2014 | A1 |
| 20140207219 | Dunbar | Jul 2014 | A1 |
| 20180064484 | Diederich et al. | Mar 2018 | A1 |
| 20180104407 | Dacey, Jr. et al. | Apr 2018 | A1 |
| 20180193078 | Rajagopalan et al. | Jul 2018 | A1 |
| 20190038456 | Chabal et al. | Feb 2019 | A1 |
| 20190142630 | Drnek et al. | May 2019 | A1 |
| 20190262626 | De Taboada et al. | Aug 2019 | A1 |
| 20200008973 | Dunbar et al. | Jan 2020 | A1 |
| 20200050248 | Smith | Feb 2020 | A1 |
| 20200345537 | Dunbar et al. | Nov 2020 | A1 |
| 20210145632 | Dunbar et al. | May 2021 | A1 |
| 20220085628 | Stephan | Mar 2022 | A1 |
| 20230218432 | Chabal et al. | Jul 2023 | A1 |
| Number | Date | Country |
|---|---|---|
| 2860977 | Jan 2022 | CA |
| 102227198 | Oct 2011 | CN |
| 112533561 | Mar 2021 | CN |
| 201920906490.X | Apr 2021 | CN |
| 113330659 | Aug 2021 | CN |
| 102010016404 | Dec 2012 | DE |
| 1462073 | Sep 2004 | EP |
| 2356958 | Aug 2011 | EP |
| 2665457 | Jun 2019 | EP |
| 3761925 | Jan 2021 | EP |
| 3903402 | Nov 2021 | EP |
| 62-44255 | Feb 1987 | JP |
| 05-007613 | Jan 1993 | JP |
| 05-161691 | Jun 1993 | JP |
| H0576435 | Oct 1993 | JP |
| 2004064726 | Feb 2004 | JP |
| 2007500444 | Jan 2007 | JP |
| 2007531562 | Nov 2007 | JP |
| 2008513743 | May 2008 | JP |
| 2008539953 | Nov 2008 | JP |
| 2009537226 | Oct 2009 | JP |
| 2016538972 | Dec 2016 | JP |
| 6502612 | Apr 2019 | JP |
| 2665457 | Oct 2019 | JP |
| 2020110662 | Jul 2020 | JP |
| 2021517024 | Jul 2021 | JP |
| 6923501 | Aug 2021 | JP |
| 2022517538 | Mar 2022 | JP |
| 200382853 | Apr 2005 | KR |
| 1020080095279 | Sep 2005 | KR |
| 1020150127108 | Nov 2015 | KR |
| 101603078 | Mar 2016 | KR |
| WO1987002891 | May 1987 | WO |
| WO2005079295 | Sep 2005 | WO |
| WO2006086513 | Aug 2006 | WO |
| WO2008057884 | May 2008 | WO |
| WO2009073208 | Jun 2009 | WO |
| WO2009073223 | Jun 2009 | WO |
| WO2009075783 | Jun 2009 | WO |
| WO2011127918 | Oct 2011 | WO |
| WO2014088768 | Jun 2014 | WO |
| WO2015054615 | Apr 2015 | WO |
| WO2012100258 | Jan 2018 | WO |
| WO2019173623 | Sep 2019 | WO |
| WO2020139883 | Jul 2020 | WO |
| WO2021247765 | Dec 2021 | WO |
| Entry |
|---|
| International Search Report and Written Opinion, issued for International Application No. PCT/US2021/035536, Mailing Date: Nov. 18, 2021, 25 pages. |
| ISA, International Search Report and Written Opinion, issued for International Application No. PCT/US2006/004506, Applicant: Carewave, Inc. Mail Date: Sep. 24, 2007, 7 pages. |
| ISA, International Search Report and Written Opinion, issued for International Application No. PCT/US2006/004506, Mail Date: Sep. 25, 2007, 10 pages. |
| ISA, International Search Report and Written Opinion, issued for International Application No. PCT/US2019/068477, Mail Date: May 12, 2020, 14 pages. |
| Official Notice of Rejection for JP Patent Application No. 2018-212186, dated Sep. 29, 2020, 7 pages (with unofficial translation). |
| Requisition by the Examiner for Canadian Application No. 2,860,977 dated Jan. 25, 2021 (3 pages). |
| Official Notice of Rejection for Japanese Patent Application No. 2020-069050 dated Apr. 27, 2021, 8 pages. |
| Notice of Allowance for Japanese Patent Application No. 2018-212186 dated Jun. 29, 2021, 6 pages. |
| European Extended Search Report, issued for EP Application No. 19763965.1, Mail Date: Nov. 9, 2021, 9 pages. |
| Requisition by the Examiner for Canadian Application No. 2,860,977 dated Oct. 18, 2019 (4 pages). |
| Non-Final Office Action, issued for U.S. Appl. No. 16/154,036, Applicant: Ralph G. Dacey, JR., mailed Apr. 30, 2020, 34 pages. |
| Non-Final Office Action, issued for U.S. Appl. No. 17/065,817, Applicant: Peter J. Dunbar, mailed Nov. 8, 2022, 35 pages. |
| Application Note-Rat Sciatic Nerve; Aculight corporation; bearing a date of Dec. 6, 2006; pp. ⋅ 1-2. |
| Belverud, Shawn; Mogilner, Alon; Schulder, Michael; Intrathecal Pumps; Neurotherapeutics: The Journal of the American Society for Experimental Neuro Therapeutics; Jan. 2008; pp. 114-122; vol. 5, No. 1. |
| Binshtok, Alexander M.; Bean, Bruce P.; Woolf, Clifford J.; Inhibition of Nociceptors by TRPVI-Mediated Entry of Impermeant Sodium Channel Blockers; Nature, Letters; bearing a date of Oct. 4, 2007; pp. 607-661 ⋅ 1; vol. 449; Nature Publishing Group. |
| Bjordal, Jan M.; Johnson, Mark I.; Lopes-Martins, Rodrigo AB; Bogen, Bard; Chow, Roberta; Ljunggren, Anne E.; Short-Term Efficacy of Physical Interventions in Osteoarthritic Knee Pain. A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials.; BMC Musculoskeletal Disorders, BioMed Central; 2007; pp. 1-34, plus cover page and Figs. 1-8; vol. 8, No. 51; Bio Med Centrai Ltd.; located at: http:i/wwvv.biomedcentral.com/14 71-24 74/8/51. |
| Boggs, Will; Physical Interventions can be Effective for Osteoarthritic Knee Pain; VVebMD; 1994-2007; pp. 1-2; Medscape; located at: http://www.medscane.com/viewarticle/559501; printed on Jul. 12, 2007. |
| Bostock, Hugh; Cikurel, Katia; Burke, David; Invited Review: Threshold Tracking Techniques in the Study of Human Peripheral Nerve; Muscle & Nerve; Feb. 1998; pp. 137-158; John Wiley & Sons, Inc. |
| Brooks, Jonathan; Tracey, Irene; Review: From Nociception to Pain Perception: Imaging the Spinal and Supraspinal Pathways; Journal of Anatomy; 2005; pp. 19-33; vol. 207; Anatomical Society of Great Britain and Ireland. |
| Burdakov, Denis; Gerasimenko, Oleg; Verkhratsky, Alexei; Brief Communication: Physiological Changes in Glucose Differentially Modulate the Excitability of Hypothalamic Melanin-Concentrating Hormone and Orexin Neurons In Situ; The Journal of Neuroscience; bearing a date of Mar. 2, 2005; pp. 2429-2433; vol. 25, No. 9. |
| Could Nerve-Snip Spur Weight Loss?; CNN.corn; 2007; pp. 1-2; Cable News Network; located at: http://www.crm.corn/2007/HEAL TH/conditions/07/09/obesity.nerve.ap/index.html; printed on Jul. 12, 2007. |
| Device blocking stomach nerve signals shows promise in obesity, physorg.com, Mayo Clinic, bearing a date of Jun. 26, 2008, pp. 1-2; located at http://www.pilysorg.com/news/33701913.htrnl. |
| Douglas, W.W.; Malcom, J.L.; The Effect of Localized Cooling on Conduction in Cat Nerves; Journal of Physiology; 1955; pp. 53-71; vol. 130; located at: jp.physoc.org. |
| Fang, Zi-Ping; Mortimer, J. Thomas; Selective Activation of Small Motor Axons by Quasitrapezoidal Current Pulses; IEEE Transactions on Biomedical Engineering; Feb. 1991; pp. 168-174; vol. 38, No. 2; IEEE. |
| Franz, D.N.; lggo, A.; Conduction Failure in Myelinated and Non-Myelinated Axons at Low Temperatures; Journal of Physiology; 1968; pp. 319-345; vol. 199. |
| Gordon, Ryan D.; Peterson, Tim A; 4 Myths About Transdermal Drug Delivery; Drug Delivery Technology; bearing a date of Jun. 4, 2003 and posted on Mar. 28, 2008; pp. 1-9; vol. 3, No. 4. |
| Grayson, Amy C. Richards; Shawgo, Rebecca S.; Johnson, Audrey M.; Flynn, Nolan T.; Li, Yawen; Cima, Michael J.; Langer, Robert; A BioMEMS Review: MEMS Technology for Physiologically Integrated Devices; Proceedings of the IEEE; bearing a date of Jan. 2004; pp. 6-21; vol. 92, No. 1. |
| Han, Xue; Boyden, Edward S., Multiple-Color Optical Activation, Silencing, and Desynchronization of Neurai Activity, with Single-Spike Temporal Resolution; PLoS ONE; Mar. 2007; pp. 1-12; Issue 3, No. e299; located at www.piosone.org. |
| Harland, C.J.; Clark, T.D.; Prance, R.J.; Remote Detection of Human Electroencephalograms Using Ultrahigh Input Impedance Electric Potential Sensors; Applied Physics Letters; bearing a date of Oct. 21, 2002; pp. 3284-3286; vol. 81, No. 17; American institute of Physics. |
| Hinrikus, H.; Lass, J.; Tuulik, V.; Low-Level Microwave Effect on Nerve Pulse Propagation Velocity; Proceedings of the 25th Annual International Conference of the IEEE EMBS; bearing dates of Sep. 17, 2003-Sep. 21, 2003; pp. 3253-3256; IEEE. |
| Hodgkin, A.L.; Huxley, A.F.; A Quantitative Description of Membrane Current and its Application to Conduction and Excitation in Nerve; Journal of Physiology; 1952; pp. 500-544;voi. 117. |
| Hong, CZ; Reversible Nerve Conduction Block in Patients with Polyneuropathy After Ultrasound Thermotherapy at Therapeutic Dosage.; Archives of Physical Medicine and Rehabilitation; Feb. 1991, pp. 132-137, only the abstract is being provided; vol. 72, No. 2; located at: http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=PubMed&list-uids=1846738&dont=AbstractPlus; printed on May 9, 2007. |
| Howarth, Peter H.; Persson, Carl G.A.; Meitzer, Eli O.; Jacobson, Mikila R.; Durham, Stephen R.; Silkoff, Philip E.; Objective Monitoring of Nasal Airway Inflammation in Rhinitis; Journal of Allergy Clin Immunol; Mar. 2005; pp. S414-S441; American Academy of Ailergy, Asthma and Immunology. |
| Hsieh, Dean S. T.; Langer Robert; Folkman, Judah; Magnetic Modulation of Release of Macromolecules from Polymers; Proc. Natl. Acad. Sci. USA; bearing a date of Mar. 1981; pp. 1863-⋅J 867; vol. 78. No. 3. |
| Hsu, Kai-Hsiung; Durand, Dominique M., Prediction of Neural Excitation During Magnetic Stimulation Using Passive Cable Models; IEEE Transactions on Biomedical Engineering; Apr. 2000; pp. 463-471; vol. 47, No. 4; IEEE. |
| Hsu, Kai-Hsiung; Durand, Dominique M.; A 3-D Differential Coil Design for Localized Magnetic Stimulation; IEEE Transactions on Biomedical Engineering; Oct. 2001; pp. 1162-1168; vol. 48, No. 1 O; IEEE. |
| Hsu, Kai-Hsiung; Nagarajan, Srikantan S.; Durand, Dominique M.; Analysis of Efficiency of Magnetic Stimulation; IEEE Transactions on Biomedical Engineering; Nov. 2003; pp. 1276-1285; vol. 50, No. 11; IEEE. |
| Kane, D.; Lockhart, JC; Balint, PV; Mann, C.; Ferrell, WR; Mcinnes, 18; Protective Effect of Sensory ⋅ enervation in Inflammatory Arthritis (evidence of regulatory neuroimmune pathways in the arthritic joint); ARD Online, Ann. Rheum. Dis.; 2005; pp. 325-327 plus cover page; vol. 64; located at: www.annrheumdis.com. |
| Kilani, Ruhangiz T.; Maksymowych, Walter P.; Aitken, Alastair; Boire, Gilles; St. Pierre, Yves; U, Yunyuan; Ghahary, Aziz; Detection of High Levels of 2 Specific Isoforms of 14-3-3 Proteins in Synovial Fluid from Patients with Joint Inflammation; The Journal of Rheumatology; 2007; pp. 1650-1657; vol. 34, No. 8. |
| Kilgore, K.L.; Bhadra, N.; Nerve Conduction Block Utilising High-Frequency Alternating Current; Medicai & Biological Engineering & Computing; 2004; pp. 394-406; voi. 42; IFMBE. |
| Krasteva, Vessela TZ; Papazov, Sava P.; Daskalov, Ivan K.; Peripheral Nerve Magnetic Stimulation: Influence of Tissue Non-Homogeneity; BioMedical Engineering on line; 2003; pp. 1-14; located at: http://www.biomedicalengineering-online.com/content/2/1 /19. |
| Krauthamer, V.; Crosheck, T.; Effects of High-Rate Eiectrical Stimulation Upon Firing in Modelled and Real Neurons; Medical & Biological Engineering & Computing; 2002; pp. 360-366; vol. 40; IFMBE. |
| Kuwabara, Satoshi; Cappelen-Smith, Cecilia; Lin, Cindy S.-Y.; Mogyoros, Ilona; Bostock, Hugh; Burke, David; Excitabiiity Properties of Median and Peroneai Motor Axons; Muscle and Nerve; Sep. 2000; pp. 1365-1373; vol. 23. |
| Lam, FY; Ferrell, WR; Neurogenic Component of Different Models of Acute Inflammation in the Rat Knee Joint.; Published, NCBI, Ann. Rheum. Dis.; Nov. 1991; pp. 747-751, only the abstract is enclosed; vol. 50, No. 11; printed on May 17, 2007. |
| Lele, P.P ; Effects of Focused Ultrasonic Radiation on Peripheral Nerve, with Observations on Local Heating; Experimental Neurology; 1963; pp. 47-83; vol. 8. |
| Lin, Cindy S.-Y.; Mogyoros, Ilona; Kuwabara, Satoshi; Cappelensmith, Cecilia; Burke, David; Accommodation to Depolarizing and Hyperpolarizing Currents in Cutaneous Afferents of the Human Median and Sural Nerves; The Journal of Physiology Online; J, Physiol. 2000; pp. 483-492; vol. 529; located at: http://www.jp.physoc.org/cgi/content/full/529/2/483; printed on Oct. 5, 2007. |
| Local Anaesthetics and Nerve Conduction; The Virtual Anaesthesia Textbook; bearing a date of 2000; pp. 1-2; located at: http://www.virtual-anaesthesia-textbook.corn. |
| Ma, Qing-Ping; Vanilloid Receptor Homologue, VRU, is Expressed by Both A and C-Fiber Sensory Neurons NeuroReport, Somatosensory Systems, Pain; bearing a date of Dec. 4, 2001; pp. 3693-3695; vol. 12, No. 17; Lippincott Williams & Wil. |
| Makers of ActiPatch(TM) a Drug-Free, Anti-Inflammatory Patch that Resolves Swelling BioElectronics; 2004; pp. 1-4; BioElectronics Corp. |
| Marks, William 8.; Loeb, Gerald E.; Action Currents, Internodal Potentials, and Extracellular Records of Myelinated Mammalian Nerve Fibers Derived from Node Potentials; Biophysical Journal; 1976; pp. 655-668; vol. 16. |
| McCleskey, Edwin W.; Neuroscience: A Local Route to Pain Relief; Nature—News & Views; bearing a date of Oct. 4, 2007; pp. 545-546; vol. 449; Nature Publishing Group. |
| McNeal, Donald R.; Analysis of a Model for Excitation of Myelinated Nelve; IEEE Transactions on Biomedical Engineering; Jul. 1976; pp. 329-337; vol. BME-23, No. 4. |
| Norton, Stephen J., Research: Can Ultrasound be Used to Stimulate Nerve Tissue ?; BioMedical Engineering Online; 2003; pp. 1-9; vol. 2, No. 6; Bio Med Central Ltd.; located at: http://www.biomedical-eng ineering-onl ine. com/content/2/1 /6. |
| Orlee, Kenneth S., Horch, Kenneth VV.; Differential Activiation and Block of Peripheral Nerve Fibers by Magnetic Fields; Muscle and Nerve; 2006; pp. 189-196; vol. 34; located at: www.interscience.wiley.com. |
| Pareek, Tej K.; Keller, Jason; Kesavapany, Sashl; Pant, Harish C ; Ladarola, Michael J.; Brady, Roscoe O.; Kulkarni, Ashok B.; Cyelin-Dependent Kinase 5 Activity Regulates Pain Signaling; PNAS; bearing a date of Jan. 17, 2006; pp. 791-796; vol. 103, No. 3. |
| Pavlov, VA; Tracey, K.J.; Review: Neural Regulators of Innate Immune Responses and Inflammation; CMLS-Cellular and Molecular Life Sciences; 2004; pp. 2322-2331; vol. 61; Birkhiiuser Verlaa Basel. |
| PCT International Search Report; International App. No. PCT/US 08/13442; Feb. 20, 2009; pp. 1-3. |
| PCT International Search Report; International App. No. PCT/US 08/13443; Feb. 20, 2009; pp. 1-2. |
| PCT International Search Report; International App. No. PCT/US 08i13407; Feb. 20, 2009; pp. 1-2. |
| PCT International Search Report; International App. No. PCT/US2008i013406; Feb. 9, 2009; pp. 1-2. |
| Peckham; P. Hunter; Knutson; Jayme S.; Functional Electrical Stimulation for Neuromuscular Applications; Annual Reviews; 2005; pp. 327-360; located at: http://www.arjournals.annualreviews.org; printed on Feb. 13, 2007. |
| Pham-Marcou, T.A.; Gentili, 1\/1.; Asehnoune, K.; Fletcher, D.; Mazoit, J.-X.; Pain: Effect of Neurolytic Nerve Block on Systemic Carrageenan-Induced Inflammatory Response in Mice; British Journal of Anaesthesia; 2005; pp. 243-246; vol. 95, No. 2; The Board of Management and Trustees of the British Journal of Anaesthesia. |
| Poole, AR; Immunochemical Markers of Joint Inflammation; Skeletal Damage and Repair: Where are we now?; Annals of the Rheumatic Diseases; 1994; pp. 3-5; vol. 53. |
| Power, I., Review Article: Fentanyl HCI lontophoretic Transdennal System (ITS): Clinical Application of lontophoretic Technology in the Management of Acute Postoperative Pain; British Journal of Anaesthesia; bearing a date of 2007; pp. 4-11; vol. 98, No. 1. |
| Prescott, James H.; Lipka, Sara; Baldwin, Samuel; Sheppard, Jr., Norman F.; Maloney, John M.; Coppeta, Jonathan; Yomtov, Barry; Staples, Mark A.; Santini, Jr.; John T.; Brief Communications: Chronic, Programmed Polypeptide Delivery from an Implanted, Muitireservoir Microchip Device; Nature Biotechnology; bearing a date of Apr. 2006; pp. 437-438; vol. 24, No. 4; located at: www.nature.com1naturebiotechnology. |
| Product Information: Actipatch; BioElectronics, Medical Professionals Info Center; 2004; pp. 1-3; BioElectronics Corp. |
| Rattay, Frank, Aberham, Matthias; Modeling Axon Membranes from Functional Electrical Stimulation; IEEE Transactions on Biomedical Engineering; Dec. 1993; pp. 1201-1209; vol. 40, No. 12; IEEE. |
| Rattay, Frank; Analysis of Models for Extracellular Fiber Stimulation; IEEE Transactions on Biomedical Engineering; Jul. 1989; pp. 676-682; vol. 36, No. 7; IEEE. |
| Rattay; Frank; Modeling the Excitation of Fibers Under Surface Electrodes; IEEE Transactions on Biomedical Engineering; Mar. 1988; pp. 199-202; vol. 35, No. 3; IEEE. |
| Razavi, Rozita; Chan, Yin; Afifiyan, F. Nikoo; Liu, Xue Jun; Wan, Xiang; Yantha, Jason; Tsui, Hubert; Tang, Lan; Tsai, Sue; Santamaria, Pere; Driver, John P.; Serreze, David; Salter, Michael W.; Dosch, H.-Michael; TRPV1 + Sensory Neurons Control 13 Ceil Stress and Islet Inflammation in Autoimmune Diabetes; Cell; bearing a date of Dec. 15, 2006; pp. 1123-1135; vol. 127; Elsevier inc. |
| Robot Anaesthetist Developed in France: Doctor; Yahool; Agence France Press; bearing a date of Apr. 12, 2008; pp. 1-2. |
| Rooney, Terence; Bresnihan, Barry; Andersson, Ulf; Gogarty, Martina; Kraan, Maarten; Schumacher, H. Ralph; Ulfgren, Annkristin; Veale, Douglas J.; Youssef, Peter P.; Tak, Paul P.; Microscopic Measurement of Inflammation in Synovial Tissue: Inter-Observer Agreement for Manual Quantitative, Semiquantitative and Computerised Digital image Analysis; Ann Rheum Dis; 2007; pp. 1656-1660; vol. 66. |
| Roxhed, Niclas; Samel, Bjorn; Nordquist, Lina; Griss, Patrick; Stemme, Goran; Painless Drug Delivery Through Microneedle-Based Transdermal Patches Featuring Active Infusion; IEEE Transactions on Biomedical Engineering; bearing a date of Mar. 2008; pp. 1063-1071, vol. 55, No. 3. |
| Saliba, Susan; Mistry, DilaawarJ.; Perrin, David H.; Gieck, Joe; Weitman, Arthur; Original Research: Phonophoresis and the Absorption of Dexamethasone in the Presence of an Occlusive Deressing; Journal of Athletic Training; 2007; pp. 349-354; National Athletic Trainers' Association, Inc; located at: www.journalofathletictraining.com. |
| Singer, Emily; A New Way to Treat Obesity; Technology Review; bearing a date of May 15, 2008; pp. 1-3; MIT. |
| Singer, Emily; Neural Stimulation for Autoimmune Diseases; Technology Review; bearing a date of Jun. 1, 201 O; pp. 1-2; MIT. |
| Sternberg, Esther M.; Neural Regulation of Innate Immunity: A Coordinated Nonspecific Host Response to Pathogens; NIH Public Access, Author Manuscript—Nat. Rev. Immunol.; Apr. 2006; pp. 318-328 (pp. 1-26); vol. 6, No. 4. |
| Struijk, Johannes Jan; The Extracellular Potential of a Myelinated Nerve Fiber in an Unbounded Medium and in Nerve Cuff Models; Biophysical Journal; Jun. 1997; pp. 2457-2469; vol. 72; Biophysical Society. |
| Stubbe, Barbara G.; De Smedt, Stefaan C.; Demeester, Joseph; Review Programmed Polymeric Devices for Pulsed Drug Delivery; Pharmaceutical Research; bearing a date of Oct. 2004; pp. 1732-1740; vol. 21, No. 10. |
| Study Finds Nerve Damage in Previously Mysterious Chronic Pain Syndrome; Doctor's Guide, Personal Edition; 2007; pp. 1-2 (front and back); located at: http://www.docguide.com/news/content.nsflNewsPrint/852571020057CCF685257107005273F6; printed on May 9, 2007. |
| Tai, Changfeng; De Groat, William C.; Roppolo, James R.; Simulation Analysis of Conduction Block in Unmyelinated Axons Induced by High-Frequency Biphasic Electrical Currents; IEEE Transactions on Biomedical Engineering; Jul. 2005; pp. 1323-1332; vol. 52, No. 7. |
| Tokusilige, Natsuko; Markham, Robert; Russell, Peter; Fraser, Ian S ; Nelve Fibers in Peritoneal Endometriosis; Human Reproduction; 2006; pp. 3001-3007; vol. 21, No. 11. |
| Tracey, Kevin J.; Review: Physiology and Immunology of the Cholinergic Anti-infiammatory Pathway; The Journal of Clinical Investigation; Feb. 2007; pp. 289-296; vol. 117, No. 2; located at: http:i/www.jci.org. |
| Treatment Blocks Pain Without Disrupting Other Functions; published: Oct. 3, 2007; 2 pages; .. iocatedat:. http://www.physorg.com/news110637008.html. |
| Tsui, Po-Hsiang; Wang, Shyh-Hau; Huang, Chill-Chung; In Vitro Effects of Ultrasound with Different Energies on the Conduction Properties of Neural Tissue; ScienceDirect-Ultrasonics; 2005; pp. 560-565; vol. 43; Elsevier B.V.; located at: www.elsevier.com/locate/ultras. |
| UK Intellectual Property Office Examination Report under Section 18(3); Application No. GB1010163.2; Jan. 26, 2012; pp. 1-2. |
| Van Den Honert, Christopher; Mortimer, J. Thomas; A Technique for Collision Block of Peripheral Nerve: Single Stimulus Analysis; IEEE Transactions on Biomedical Engineering; May 1981; pp. 373-378; vol. BME-28, No. 5. |
| Voloshin, ilya; Gelinas, Jill; Maloney, Michael D.; O;Keefe, Regis J.; Bigliani, Louis U.; Blaine, Theodore A.; Proinflammatory Cytokines and Metallo proteases are Expressed in the Subacromial Bursa in Patients with Rotator Cuff Disease; The Journal of Arthroscopic and Related Surgery; 2005; pp. 1076e1-1076e9; vol. 21, No. 9. |
| VVells, Jonathan; Kao, Chris; Konrad, Peter; Milner, Tom; Kim, Jihoon; Mahadevan-Jansen, Anita; Jansen, E. Duco; Application of Infared Light for In Vivo Neural Stimulation; The Journal of Biomedical Optics; Nov./Dec. 2005; pp. 064003-1-064003-12; vol. 10(6). |
| VVells, Jonathan; Kao, Chris; Konrad, Peter; Milner, Tom; Kim, Jihoon; Mahadevan-Jansen, Anita; Jansen, E. Duco; Biophysical Mechanisms of Transient Optical Stimulation of Peripheral Nerve; Biophysical Journal; Oct. 2007; pp. 2567-2580; vol. 93. |
| Walsh, Raymond R.; Deal, Stanley E.; Reversible Conduction Block Produced by Lipid-Insoluble Quarternary Ammonium Ions in Cetyltrimethylammonium Bromide-Treated Nerves; Am J Physiol; 1959; pp. 547-550; Only the abstract is being provided; vol. 197; located at: http://http://ajpiegacy. physiology. org. |
| Wells, Jonathan; Konrad, Peter; Kao, Chris; Jansen, E. Duco; Mahadevan-Jansen, Anita; Pulsed Laser Versus Electrical Energy for Peripheral Nerve Stimulation; Journal of Neuroscience Methods; 2007; pp. 326-337; located at: www.elsevier.com/locate/jneurneth. |
| Windle, Mary L.; Anesthesia, Topical; E-Medicine from WebMD; Mar. 14, 2007; pp. 1-4; located at: vww.webmd.com. |
| Zhang, Xu; Roppolo, James R.; De Groat, William C.; Tai, Changfeng; Mechanism of Nerve Conduction Block Induced by High-Frequency Biphasic Electrical Currents; IEEE Transactions on Biomedical Engineering; Dec. 2006; pp. 2445-2454; vol. 53, No. 12. |
| Zhang, Xu; Roppolo, James R.; De Groat, William C.; Tai, Changfeng; Simulation Analysis of Conduction Block in Myelinated Axons Induced by High-Frequency Biphasic Rectangular Pulses; IEEE Transactions on Biomedical Engineering;Jul. 2006; pp. 1433-1436; vol. 53,No. 7. |
| European Extended Search Report EP Application No. 19763965.1, Mail Date: Nov. 9, 2021. 9 pages. |
| Adair R. “A model of the detection of warmth and cold by cutaneous sensors through effects on voltage-gated membrane channels” PNAS, Oct. 12, 1999, vol. 96, No. 21, pp. 11825-11829. |
| Bazett, H.C. et al. “The temperature in the tissues which accompany temperature sensations” Journal of Physiology, 1930, vol. 69, No. 1, pp. 88-112. |
| Dussor, G. et al. “TRPM7 and Migraine” Headache, Oct. 2016, vol. 56, No. 9, pp. 1406-1417. |
| Frey, M. “The Distribution of Afferent Nerves in the Skin” JAMA, 1906, vol. 47, No. 9, 645-648. |
| Higashi, Y. et al. “Efficacy and Safety Profile of a Topical Methyl Salicylate and Menthol Patch in Adult Patients with Mile to Moderate Muscle Strain: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled, Multicenter Study” Clinical Therapeutics, 2010, vol. 32, pp. 34-43. |
| ISA, International Search Report and Written Opinion for International Application No. PCT/US2019/021203. Mail Date: Jun. 11, 2019. 12 pages. |
| Lloyd, D. et al. “Somatosensory pleasure circuit: from skin to brain and back” Experimental Dermatology, 2015, vol. 24, pp. 321-324. |
| Morrison, I. et al. “Reduced C-afferent fibre density affects perceived pleasantness and empathy for touch” Brain: A Journal of Neurology, 2011, 11 pages. |
| Sundstrup, E. et al. “Acute Effect of Topical Menthol on Chronic Pain in Slaughterhouse Workers with Carpal Tunnel Syndrome: Triple-Blind, Randomized Placebo-Controlled Trial” Rehabilitation Research and Practice, vol. 2014, 7 pages. |
| Topp, R. et al. “The Effect of Either Topical Menthol or a Placebo on Functioning and Knee Pain Among Patients with Knee OA” Research Report, 2013; vol. 36, No. 2, pp. 92-99. |
| International Search Report and Written Opinion dated Jun. 11, 2019 for International Application No. PCT/US2019/021203, 12 pages. |
| Oral Argument in re Rose, 220 F.2d 459, 105 USPQ 237 (CCPA 1955), United States Court of Customs and Patent Appeals, 5 pages. |
| Partial European Search Report issued for EP Application No. 21816941.5, Mailing Date: May 8, 2024, 12 pages. |
| Number | Date | Country | |
|---|---|---|---|
| 20210052869 A1 | Feb 2021 | US |
| Number | Date | Country | |
|---|---|---|---|
| 62639930 | Mar 2018 | US |
