Systems, devices and methods for treating oropharyngeal disorders

Abstract

Provided herein are systems, devices, and methods for treating oropharyngeal disorders through stimulation of pharyngeal muscles. Contraction of pharyngeal muscle cells (9) is induced by activation of at least one ion channel (1) formed in muscle cells and / or nerve cells. When activated by a stimulus (3), the ion channel (4) opens, allowing ions (5) to flow into and (6) out of the cell, causing muscle contraction. This muscle contraction can be targeted to specific muscles depending on the condition being treated.

Description

[Technical field]

[0001] The present invention relates to systems, devices and processes for the treatment (or intervention) in oropharyngeal disorders, although it will be appreciated that the invention is not limited to this particular area of ​​use. [Background technology]

[0002] The mention of any prior art throughout this specification should in no way be taken as an admission that such prior art is widely known or forms part of the common general knowledge in the field.

[0003] Activation of excitable cells, such as neurons and muscle cells, can be achieved through the introduction of receptors or ion channels in these cells that respond to stimuli not normally present in normal animals (including humans). These receptors and ion channels can be engineered or selected to respond to non-physiological stimuli, such as light (optogenetics), chemicals (chemogenetics), or magnetic fields (magnetogenetics).

[0004] Optogenetics is the use of light to stimulate excitable cells by genetically modifying these cells to express light-sensitive ion channels, or opsins, in their plasma membrane.

[0005] Chemogenetics is the use of artificially engineered receptors that respond to non-physiological chemical stimuli to activate excitable cells.

[0006] Magnetogenetics is the use of magnetic stimuli to stimulate excitable cells by genetically modifying (or transfecting) these cells to express magnetically sensitive ion channels in their cell membranes.

[0007] The pharyngeal muscles surround the upper airway, enable breathing, and are responsible for a range of vital functions including speech, swallowing, and upper airway patency.

[0008] Obstructive sleep apnoea is a common sleep disorder in which muscular activity of the pharyngeal muscles is insufficient to maintain the patency of the upper airway during sleep. The upper airway repeatedly collapses during sleep, resulting in desaturation and requiring arousals to normalize. This results in sleep disruption, daytime sleepiness, and increased risk of accidents and heart disease. Stimulation of the pharyngeal dilator muscles can open and maintain the patency of the airway, including during sleep.

[0009] There are current treatments that rely on electrical stimulation of the tongue dilator muscles, which activate the hypoglossal nerve, causing the dilator muscles to constrict and open the upper airway. These systems are fully implanted and cannot provide non-invasive or minimally invasive muscle stimulation. Additionally, they are not effective for all people.

[0010] Other treatment methods, such as delivery of continuous positive airway pressure or mandibular advancement splints, have reports of sub-optimal patient tolerance and adherence, or non-universal efficacy.

[0011] Dysphagia is difficulty in swallowing. It can occur with or without pain. It can occur for a number of reasons and is commonly associated with neurological dysfunction of the pharyngeal or esophageal muscles. It can occur in a range of neurological disorders, including multiple sclerosis, muscular dystrophy, Parkinson's disease, stroke, and spinal cord or brain injury. It can also occur after trauma or surgery, or in cancer, or as a result of cancer treatment. Current treatments include physical therapy exercises, or surgical or pharmaceutical treatments, which relax the esophageal muscles to reduce distal blockage of the esophagus.

[0012] Speech disorders include difficulties in speaking or producing sounds fluently. A subset of patients with speech disorders acquire them as a result of dysfunction of the pharyngeal muscles associated with neurological diseases such as stroke, or neuromuscular degenerative disorders.

[0013] It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. Summary of the Invention

[0014] Provided herein is a system, device and method for treating oropharyngeal disorders.In some preferred embodiments, light-responsive opsin protein is used, which can activate either the motor neurons that innervate pharyngeal muscles or the muscle cells themselves, thereby inducing the contraction of pharyngeal muscles in response to light stimulation.In other preferred embodiments, magnetic or chemical stimulation is used to induce the contraction of pharyngeal muscles.

[0015] According to a first aspect, the present invention provides a system for stimulating pharyngeal muscles, said system comprising means for activation of at least one ion channel formed in muscle cells and / or nerve cells.

[0016] According to a second aspect, the present invention provides a method of stimulating a pharyngeal muscle, said method comprising activation of at least one ion channel formed in muscle cells and / or nerve cells.

[0017] Preferably, the ion channel opens when activated, thereby causing muscle contraction. Preferably, the activation means activates an exogenous receptor linked to the ion channel.

[0018] According to a third aspect, the present invention provides a system for inducing contraction of pharyngeal muscle cells, said system comprising: a delivery means configured to direct a stimulus to a target; a stimulation source configured to provide a stimulus to said delivery means; and a controller operably linked to said stimulation source.

[0019] According to a fourth aspect, the present invention provides a method of inducing contraction of pharyngeal muscle cells, said method comprising the step of directing a stimulus to a target, thereby inducing contraction of the muscle cells.

[0020] Preferably, the target is an ion channel. The ion channel is preferably formed in pharyngeal muscle cells and / or nerve cells.

[0021] Preferably, the target is an exogenous receptor linked to an ion channel, which would preferably be applied in a chemogenetic application or in a combined application involving both a chemical stimulus and another stimulus, such as a light stimulus.

[0022] Preferably, the stimulus is light acting on a cognate optogenetic target. Preferably, the stimulus is a chemical agent acting on a cognate chemogenetic target. Preferably, the stimulus is a magnetic field acting on a cognate magnetogenetic target. In some embodiments, more than one of the above stimuli may be used in combination. For example, light stimulation may be used at night for treatment, and chemical stimulation may be used during the day to block the receptors so that activation does not occur due to sunlight.

[0023] Preferably, the system and method are suitable for use as a treatment for disorders of the pharyngeal or oral musculature.Preferably, the system and method are suitable for use as a treatment for obstructive sleep apnea.Preferably, the system and method are suitable for use as a treatment for dysphagia.

[0024] Preferably, specific muscles or sub-regions of muscles are stimulated to provide targeted airway muscle control.

[0025] Preferably, the ion channel is a light-sensitive ion channel. Alternatively, the ion channel is sensitive to a magnetic field. Alternatively, the ion channel is sensitive to one or more chemicals. In preferred embodiments, the ion channel is sensitive to one or more of the foregoing.

[0026] Preferably, the ion channels are formed by delivery of genetic material to muscle cells and / or nerve cells. Preferably, the genetic material is delivered by local injection using a viral vector. The injection may be targeted to a specific location. Alternatively, the injection may be to a systemic area. In another embodiment, the genetic material is delivered by systemic delivery using a viral vector. Alternatively, the ion channels are formed by local delivery of genetic material by electroporation or other means. Preferably, the genetic material comprises modified stem cells or encapsulated cells.

[0027] Preferably, the method according to the second or fourth aspect comprises forming ion channels in at least one of pharyngeal muscle cells and neuronal cells.

[0028] Preferably, the system according to the first or third aspect comprises a mechanism for forming ion channels in at least one of pharyngeal muscle cells and neuronal cells.

[0029] Preferably, the ion channels are targeted to peripheral nerves that innervate pharyngeal muscles. Alternatively, the ion channels are targeted to pharyngeal muscle cells.

[0030] Preferably, an additional chemical or genetic control mechanism is provided to control the activity of the light-sensitive ion channel.

[0031] In some embodiments, the system is preferably activated in synchronization with the respiratory cycle. In these and other embodiments, the system may be activated on an as-needed basis, either at defined periods or intermittently. In still further embodiments, the system is preferably activated in response to partial or complete upper airway obstruction detected by an integrated pharyngeal pressure sensor or other means.

[0032] Preferably, the system includes a light source. The light source is preferably capable of generating red, amber, blue or green light. Preferably, the ion channel is activated by red, amber, blue or green light.

[0033] Preferably, the system delivers light stimuli to activate exogenous receptors linked to ion channels formed in pharyngeal muscles or nerve cells. In some embodiments, the light stimuli are delivered via one or more intraoral sources. In alternative embodiments, the light stimuli are delivered via one or more transdermal sources. In still further embodiments, the light stimuli are delivered by one or more implanted sources via optical fibers or other means.

[0034] Preferably, the system includes an intra-oral appliance. The appliance is preferably removable. Preferably, the removable appliance is worn primarily or solely during sleep. Preferably, the appliance includes a rechargeable power source.

[0035] Preferably, the oral appliance includes channels for releasable engagement with the user's teeth. Alternatively, the oral application includes loops for tooth engagement.

[0036] In an alternative embodiment, the system includes a subcutaneously implanted device. Preferably, the implanted device invasively or minimally invasively activates or stimulates ion channels.

[0037] Preferably, the system includes both internal and external components. The internal components may include removable and / or implanted components. The external components may include a power source. Power may be provided from the power source to the internal components using inductive or RF power delivery.

[0038] Preferably, the system includes at least one sensor. The sensor is preferably configured to generate an electrical signal representative of the condition of the target or its environment. Preferably, the sensor is configured to deliver a signal to a controller, and the controller is further configured to interpret the signal from the sensor and adjust the stimulation directed to the target. Preferably, the system is configured to transmit the sensed information to an external device for analysis or review by a clinician.

[0039] Preferably, the system includes at least one sensor for monitoring the user's condition. Such conditions may include, for example, the user's breathing cycle, breathing, cessation of breathing, apnea, hypopnea, diaphragmatic movement, muscle cell activity, nerve cell activity, transthoracic impedance, airway pressure, temperature, pharyngeal narrowing, or pharyngeal collapse. For example, airway pressure may indicate that the airway is partially or completely obstructed. In a further example, an accelerometer may be used to detect vibrations of the airway, which may indicate that the patient is snoring and / or provide information regarding the severity of the patient's snoring.

[0040] Preferably, when a predetermined condition is sensed, delivery of stimuli to the target is activated to induce contraction or relaxation of the pharyngeal muscles. Advantageously, specific muscles or nerve cells can be targeted, allowing control of specific areas of the pharyngeal muscles to achieve stiffening or dilation of the airway.

[0041] Alternatively, the controller may utilize a timer to deliver a predetermined stimulation strategy. In other embodiments, the delivery of stimulation may be manually controlled. For example, this may be appropriate when the stimulation is in nature or chemical for conditions such as dysphagia.

[0042] Preferably, the stimulation of the muscle is targeted to a specific location, for example, the location where collapse occurs in the airway. This can be achieved by providing stimulation to ion channels only in the targeted area. Alternatively, this can be achieved by providing stimulation to the entire pharyngeal area, but where ion channels are formed only in the area targeted for stimulation. Should the user's requirements change over time, additional ion channels can be formed in new areas for stimulation.

[0043] Preferably, the system includes a transfer means for transmitting the sensed information and / or user parameters for access by a clinician or specialist. The system may additionally or alternatively include a data storage means for storing the sensed data and / or user parameters for later access and / or review. Later access to the stored data may be via download or wireless transmission. Advantageously, ongoing collected data can be used to monitor the patient's condition and the effectiveness of treatment.

[0044] Preferably, the system may include at least one monitoring module, which may be used to monitor and / or store various user parameters and / or sensed information, as desired. The module may be configured to removably connect to the oral appliance. Alternatively, the module may be used simultaneously with the oral appliance. The monitoring module preferably includes a power source.

[0045] Embodiments of the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which: [Brief description of the drawings]

[0046] [Figure 1] FIG. 1 is a diagram showing stimulation of pharyngeal muscles using excitation of ion channels formed in muscle or nerve cell membranes for the treatment of sleep apnea. [Diagram 2] FIG. 2 is a flow chart illustrating a method for stimulating pharyngeal muscles in accordance with the present invention. [Diagram 3] FIG. 3 is a rear perspective view of a first embodiment of an oral appliance in accordance with the present invention. [Figure 4] FIG. 4 is a front perspective view of the oral appliance shown in FIG. [Diagram 5] FIG. 5 is a rear perspective view of a second embodiment of an oral appliance in accordance with the present invention. [Figure 6] FIG. 6 is a side view of an oral appliance according to a third embodiment of the present invention shown implanted in a user. [Figure 7] FIG. 7 is a diagram showing the measurement of the effect of pharyngeal muscle stimulation by optical activation. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0047] Preferred embodiments of the present invention Although the present invention has been described with reference to certain embodiments detailed herein, other embodiments can achieve the same or similar results. Variations and modifications of the present invention will be obvious to those skilled in the art, and the present invention is intended to cover all such modifications and equivalents.

[0048] A preferred embodiment of the present invention will now be described, by way of example only, with reference to the accompanying drawings, in which:

[0049] As best seen in Figure 1, ion channels 1 formed in muscle or nerve cells are 2 closed when the cell is inactive. A stimulus 3 in the form of light, a magnetic field or a chemical is applied, causing the ion channels 4 to open. This allows ions 5 to flow in and 6 to flow out of the cell, thereby activating the cell. 7 When ion channels are formed in muscle cells, activation of the muscle cell occurs through the Ca2+ 8 into the muscle. This causes the relative movement of actin and myosin, resulting in muscle cell contraction. Alternatively, if the ion channel is located in a nerve cell, activation of the nerve cell will send an action potential to the neuromuscular junction on the corresponding muscle cell, activating the muscle cell. This is because Ca 2+ similarly enters the muscle, causing relative movement of actin and myosin, resulting in muscle cell contraction. In this example application, for the treatment of sleep apnea, the resulting contraction of the pharyngeal dilator muscles 9 causes the opening of the airway 10. In alternative applications, such as for the treatment of dysphagia or speech disorders, stimulation can be directed to different muscles to produce different effects, such as tongue movement or swallowing.

[0050] The ion channel is not naturally occurring and needs to be formed in the user's muscle cells and / or nerve cells, which may occur prior to application of the present invention. Alternatively, the systems and methods according to the present invention may include mechanisms or steps for the formation of ion channels in at least one of the muscle cells and nerve cells, respectively.

[0051] The ion channels are formed by delivery of genetic material to muscle cells and / or nerve cells. In some embodiments, the genetic material is delivered by local injection using a viral vector. The injection can be targeted to a specific location. Alternatively, the injection can be to a systemic area. In another embodiment, the genetic material is delivered by systemic delivery using a viral vector. Alternatively, the ion channels are formed by local delivery of genetic material by electroporation or other means. Preferably, the genetic material comprises modified stem cells or encapsulated cells.

[0052] Referring now to FIG. 2, a preferred method of stimulating pharyngeal muscles according to the present invention is shown. In this embodiment, a sensor 11 detects a predetermined scenario, such as pharyngeal narrowing, pharyngeal collapse, or a phase of the respiratory cycle. An associated controller 12 sends a signal to a stimulus generator 13, which may be connected directly or via a wireless connection. This signal instructs the stimulus generator to provide a stimulus in the form of light, chemicals, or a magnetic field to ion channels formed in the cells of the user. As previously described, providing a stimulus to the ion channels activates the associated cells, thereby causing contraction of the pharyngeal muscles 14. As shown in this diagram, this muscle contraction can be used to achieve airway dilation 15, airway stiffening 16, or local pharyngeal muscle control 17 in the user.

[0053] As best shown in Figures 3 and 4, one preferred embodiment of system 18 includes an intraoral appliance or device 19. The device includes grooves 20 configured to comfortably engage with a user's teeth, thereby aiding in retention of the device within the oral cavity. Device 19 includes delivery means, shown in the form of multiple delivery sites 21, for delivering stimulation from a stimulation source (not shown) to at least one ion channel formed in a muscle or nerve cell.

[0054] Alternatively, another embodiment of the device shown in Figure 5 includes a roof portion 22 which can provide an additional or alternative delivery site location 23 to the embodiment shown in Figures 3 and 4. In a still further embodiment (not shown), the device can be configured similar to an orthodontic retainer or plate, with wire loops or another removable fastening mechanism for retaining the device in the user's mouth.

[0055] It will be appreciated that the stimulus may be light, chemical or magnetic in nature and the delivery means and stimulus source will correspond to the stimulus being delivered, for example, if the stimulus is light, the system may generate red, amber, blue or green light and the ion channels are responsive to red, amber, blue or green light.

[0056] For chemical stimulation, one technique that could be used is simply targeting engineered receptors that are activated by synthetic ligands (RASSLs). The most common version of this is designer receptors exclusively activated by designer drugs (DREADDS), which target g-protein coupled receptors. Typically, clozapine-N-oxide (CNO) is the ligand, and clozapine-sensitive receptors are engineered and then expressed in the target cells. The receptors are activated by delivering the ligand clozapine-N-oxide to the animal, often intraperitoneally, although many options exist (even eye drops). When used with the present invention, this can be delivered from a local reservoir (e.g., timed to be released at certain times of the day at a specific location on the tongue), via a delayed biodegradable material as part of an oral device, nanoparticle oral delivery, etc. Engineered receptors can be delivered in the same way as optogenetic constructs, i.e., via local injection or other routes, using viral vectors. In the present invention, the genetic material for creating the engineered receptor will likely be delivered using local injection, but electroporation or other techniques can also be used. Also, the genetic material for the receptor can be targeted to nerve or muscle cells by using cell type specific promoters. There are other RASSLs that are activated by a range of drugs, but CNO is the most common drug used.

[0057] In some embodiments, two or more of the above stimuli may be used in combination, for example, a light stimulus may be utilized during the night and a chemical stimulus may be used during the day to block receptors so that ion channels are not activated by sunlight.

[0058] The device includes a controller (not shown) operably linked to the stimulation source. In some embodiments, the controller may utilize a timer to deliver a predetermined stimulation strategy. In other embodiments, the delivery of the stimulation may be manually controlled. For example, this may be appropriate when the stimulation is chemical in nature or for the treatment of a condition such as dysphagia.

[0059] The device 19 includes an integrated sensor 24 for identification of treatment status. The sensor may be used to monitor any one or more of the following parameters: the user's respiratory cycle, breathing, cessation of breathing, apnea, hypopnea, diaphragmatic movement, muscle cell activity, neuronal activity, transthoracic impedance, airway pressure, temperature, pharyngeal narrowing, or pharyngeal collapse. For example, airway pressure may indicate that the airway is partially or completely obstructed. An accelerometer may be used to detect vibrations in the airway. These vibrations may provide information regarding whether the patient is snoring and / or the severity of the patient's snoring.

[0060] Each sensor is configured to generate an electrical signal representative of the parameter to be monitored. The sensors are configured to deliver the signal to a controller, which is further configured to interpret the signal from the sensor and adjust the stimulus directed to the target. That is, when a predetermined condition is sensed, delivery of the stimulus to the target ion channel operates to induce contraction or relaxation of the pharyngeal muscles. Advantageously, specific muscles or nerve cells can be targeted, allowing control of specific regions of the pharyngeal muscles to achieve stiffening or dilation of the airway, as desired.

[0061] In the embodiment shown in Figures 3 and 5, the sensors 24 are shown at the end of the device and, when in use, they will be located near the rear of the user's oral cavity. However, it will be appreciated that the sensors may be located anywhere on the device. The location of the sensor may depend on the parameter that requires monitoring.

[0062] As shown in FIG. 6, another preferred embodiment of the system includes an implantable system 25. The system 25 includes an implanted control component 26, which may include a power source, a stimulus source, and a control module. The control component 26 may connect wirelessly or via wires or fluid communication (e.g., for chemical stimuli) to a stimulus delivery site 28 located in the oral cavity. The stimulus delivery site may be implanted, for example, in the tongue, and may provide the stimulus invasively. Alternatively, stimulus delivery may occur by a minimally invasive approach, for example, the delivery site is located on a removable component that is located in the oral cavity. The stimulus delivered from the delivery site activates or stimulates an ion channel.

[0063] The system may also be configured to transmit sensed information to an external device for analysis or review by a clinician.

[0064] The user may require monitoring for a period of time. In some embodiments, the system may include a monitoring module including a sensor and a power source 29. Such a module may be connected to the system 18, 25 or may be used separately to gather information about the user. In some embodiments, the system includes a transfer means for transmitting sensed information and / or user parameters for access by a clinician or specialist. The system may also or alternatively include a data storage means for storing sensed data and / or user parameters for later access and / or review. Later access to the stored data may be via download or wireless transmission. Advantageously, ongoing collected data may be used to monitor the patient's condition and the effectiveness of treatment.

[0065] The system may optionally include separable monitoring modules that may be connected to and separated from the oral appliances, which may be used to monitor and / or store various user parameters and / or sensed information, as desired.

[0066] FIG. 7 is a series of diagrams showing the effect of pharyngeal muscle stimulation by optical activation.

[0067] In the experiments leading to the data shown in Figure 7, the following method was used. The genioglossus of rats was transduced with channelrhodopsin 2 (ChR2) fused to a fluorescent reporter (yellow fluorescent protein, YFP) after local injection of a 10 uL solution containing adeno-associated virus (AAV) serotype 9 containing a robust pan-cellular "CAG" motor (chicken beta-actin gene). The expression vector (AAV9-CAG-ChR2-YFP) was suspended in a solution of phosphate-buffered saline. Functional ChR2 expression was observed 4 weeks after intramuscular injection. Electromyographic activity of the genioglossus was evoked by photostimulation applied to the tongue surface with a 470 nm laser operating at 10 Hz over a range of pulse widths (1-20 ms). Effective stimulation occurred with laser powers of 1-10 mW.

[0068] 7A shows electromyographic (EMG) measurements of genioglossus muscle activity during the respiratory cycle. A 10 Hz light stimulus was applied at the tongue surface for 10 seconds, represented by a blue bar 30. Prior to the applied stimulus, genioglossus muscle activity is in phase 31, corresponding to the cyclic nature of the respiratory cycle. During the stimulus, tonic genioglossus muscle activity 32 is also induced. When the light stimulus is turned off, the tonic activity also ceases.

[0069] 7B shows the integrated genioglossus activity during the respiratory cycle. A light stimulus is applied during inspiration for 60 seconds, as shown by the blue lines 33. As shown, this stimulus induces an increase in genioglossus activity synchronized with inspiration.

[0070] 7C shows light stimulation 34 applied in synchronization with the respiratory cycle, with the diaphragmatic EMG signal 35 representative of the respiratory cycle. Three different levels of isoflurane (ISO) were used to induce corresponding levels of muscle deactivation: 2.5% ISO, 3% ISO and 3.5% ISO.

[0071] When 2.5% ISO is applied to the integrated genioglossus activity in FIG. 7B, it can be seen that the activity is similar. When 3% ISO is applied, the integrated genioglossus activity is decreased. When 3.5% ISO is applied, the integrated genioglossus activity is further decreased, resulting in atonia 36 of genioglossus activity. The decreased muscle activity results in a situation where the airway may close partially or completely.

[0072] Application of light stimulus 34 induces activation of the genioglossus muscle, which, as shown in genioglossus EMG trace 37 and diaphragm EMG trace 35, supplements inspiratory activity at 2.5% and 3% ISO applications and provides inspiratory activity in the absence of background inspiratory activity at 3.5% ISO.

[0073] In use, for example, for the treatment of sleep apnea, the device 19 is inserted by the user into their oral cavity before going to bed. Here, the device is primarily or solely worn while sleeping, however, it will be appreciated that for other conditions, the device 19 may be worn at other times. For example, in the treatment of dysphagia, the appliance may be worn during meal times. Alternatively, the system may be implanted, as shown in FIG.

[0074] When a predetermined condition is sensed, for example, a predetermined level of airway pressure indicating a partial obstruction of the airway, a stimulus is delivered to the identified ion channel, which causes the ion channel to open, thereby inducing a muscular contraction in the target muscle. Alternatively, the system may operate in synchrony with the respiratory cycle.

[0075] Specific muscles or sub-regions of muscles are stimulated to provide targeted muscle control. For example, muscle stimulation can be targeted to the location where collapse is occurring in the airway. This can be achieved by providing stimulation to ion channels in only the targeted region. Alternatively, this can be achieved by providing stimulation to the entire pharyngeal region, but where ion channels are formed only in the targeted region for stimulation. Should user requirements change over time, additional ion channels can be formed in new regions requiring stimulation.

[0076] Further applications of the present invention may include targeting genetically defined pharyngeal afferents to suppress coughing or hiccups during sleep, affect swallowing, or boost genioglossus EMG. For example, nocturnal involuntary coughing may be suppressed by chronic chemogenetic inhibition of pharyngeal afferents. Genioglossus EMG activity may be increased by either acute or chronic activation of negative pressure pharyngeal afferents.

[0077] definition In describing and claiming the present invention, the following terms are used in accordance with the definitions set forth below. It is also to be understood that the terms used herein are for the purpose of describing only particular embodiments of the present invention and are not intended to be limiting. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains.

[0078] The term "about" as used herein can mean within 1 or more standard deviations per the practice in the art. Alternatively, "about" can mean within a range of 20%. When a specific value is provided in the present specification and claims, the meaning of "about" should be considered to be within an acceptable error range for that specific value.

[0079] In the context of the present invention, the term "subject" includes any human or non-human animal. The term "non-human animal" includes all vertebrates, e.g., mammals, non-mammals, e.g., non-human primates, horses, cows, dogs, etc.

[0080] In the context of the present invention, the words "comprise", "comprising" and the like are to be interpreted inclusively as opposed to their exclusive meaning, which means "including, but not limited to".

[0081] "Preferred" and "preferably" refer to embodiments of the invention that may offer certain advantages, under certain circumstances. However, other embodiments may be preferred, under the same or other circumstances. Furthermore, the recitation of one or more preferred embodiments does not imply that other embodiments are not useful, and is not intended to exclude other embodiments from the scope of the invention.

[0082] Except in the operating examples or where otherwise noted, all numbers expressing amounts of ingredients or reaction conditions used herein are to be understood as modified in all cases by the term "about."

[0083] Unless otherwise indicated, throughout this specification, references using terms such as "processing," "computing," "calculating," "determining," "analyzing," and the like refer to the acts and / or processes of a computer or computing system or similar electronic computing device that processes and / or converts data represented as physical, e.g., electrical, quantities into other data similarly represented as physical quantities.

[0084] Similarly, the terms "controller" or "processor" can refer to any device or portion of a device that processes electronic data, e.g., from a register and / or memory, to convert the electronic data into other electronic data that can be stored, e.g., in a register and / or memory. A "computer" or "calculating machine" or a "computing platform" can include one or more processors.

[0085] References throughout this specification to "one embodiment," "some embodiments," or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment of the disclosure. Thus, the appearances of the phrases "one embodiment," "some embodiments," or "an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner, as would be apparent to one of ordinary skill in the art from this disclosure, in one or more embodiments.

[0086] In the claims below and in the description of this specification, any term comprising, comprised of or which comprises is an open term meaning to include at least the following elements / features, and is not meant to exclude others. Thus, when the term comprising is used in the claims, it should not be interpreted as being limiting to the means or elements or steps listed thereafter. For example, the scope of an expression such as a device comprising A and B should not be limited to a device consisting of elements A and B only. Also, any term including or which includes or that includes used in this specification is an open term meaning to include at least the following elements / features, and is not meant to exclude others. Thus, including is synonymous with and means comprising.

[0087] In the foregoing description of exemplary embodiments of the present disclosure, it should be recognized that various features of the disclosure are sometimes grouped together in a single embodiment, figure or description for the purpose of streamlining the disclosure and aiding in the understanding of one or more various inventive aspects. This method of disclosure, however, should not be interpreted as reflecting an intention that the claims require more features than are expressly recited in each claim. Rather, as the following claims reflect, inventive aspects lie in less than all features of a single prior-disclosed embodiment. Thus, the claims following the detailed description are hereby expressly incorporated into this detailed description, with each claim standing on its own as a separate embodiment of the present disclosure.

[0088] Moreover, although some embodiments described herein include certain features and not other features included in other embodiments, it is meant that combinations of features of different embodiments are within the scope of the disclosure and form different embodiments as would be understood by one of ordinary skill in the art. For example, in the following claims, any of the claimed embodiments can be used in any combination.

[0089] In the description provided herein, numerous specific details are set forth. However, it will be understood that embodiments of the present disclosure may be practiced without these specific details. In other instances, well-known methods, structures and techniques have not been shown in detail in order not to obscure an understanding of this description.

[0090] Similarly, it should be noted that the term coupled, when used in the claims, should not be construed as being limited to indicating only connection. The terms "coupled," "connected," "attached," and / or "coupled," along with their derivatives, may be used. It should be understood that these terms are not intended as synonyms for each other. Thus, the scope of the expression device A coupled to device B should not be limited to devices or systems in which the output of device A is directly coupled to the input of device B. It is meant that there is a path between the output of A and the output of B, which may be a path involving other devices or means. "Coupled" means that two or more elements are either in direct physical, electrical, or optical contact, or that two or more elements are not in direct contact with each other, but still cooperate or interact with each other. In contrast, when referring to a component being "directly coupled," "directly attached," and / or "directly coupled" to another component, there are no intervening elements present.

[0091] Various aspects of the present devices, systems, and methods may be described in terms of one or more exemplary embodiments. As used herein, the term "exemplary" means "serving as an example, example, or illustration," and should not necessarily be construed as preferred or advantageous over other embodiments disclosed herein.

[0092] Thus, while what are believed to be preferred embodiments of the present disclosure have been described, those skilled in the art will recognize that other and further modifications may be made thereto without departing from the spirit of the disclosure, and it is intended to claim all such changes and modifications as being within the scope of the present disclosure. For example, any formulas given above are merely representative of procedures that may be used. Functionality may be added or deleted from the block diagrams, and operations may be interchanged among functional blocks. Steps may be added or deleted to methods described within the scope of the present disclosure.

[0093] Recitation of numerical ranges using endpoints includes all numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.80, 4, 5, etc.).

[0094] The term "treating" or "treatment" as used herein includes reversing, reducing, or preventing symptoms, clinical signs, and the underlying pathology of a condition in a manner that improves or stabilizes the condition of a subject. As used herein and as is well understood in the art, "treatment" is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results include, but are not limited to, detectable or undetectable alleviation or remission of one or more symptoms or conditions, reduction in the extent of disease, a stable (i.e., non-worsening) state of disease, prevention of disease spread, delay or slowing of disease progression, remission or palliation, and alleviation (either partial or total) of a disease state. "Treatment" can also mean prolonging survival compared to expected survival (if not receiving treatment).

[0095] As used herein, a therapeutic to prevent a disease or condition refers to reducing the occurrence of a disease or condition in a treated sample relative to an untreated control sample, or delaying the onset or reducing the severity of one or more symptoms of a disease or condition in a statistical sample relative to an untreated control sample.

Claims

1. 1. A system for stimulating at least one pharyngeal muscle cell, the system comprising: intraoral appliances, a controller operably linked to the stimulation source; the oral appliance includes the stimulation source, the stimulation source configured for in vivo activation of at least one ion channel formed in at least one pharyngeal muscle cell or at least one neural cell associated with a pharyngeal muscle cell; the oral appliance including a channel configured to engage a user's tooth; The system, wherein the stimulus is light that acts on an optogenetic target.

2. 1. A system for inducing contraction of at least one pharyngeal muscle cell, the system comprising: an intraoral device configured to deliver an in vivo stimulus to at least one ion channel formed in at least one of a pharyngeal muscle cell and a neuronal cell associated with the pharyngeal muscle cell; a stimulation source configured to provide the stimulation through the oral appliance; and a controller operably connected to the stimulation source; Including, the oral appliance is removable from the oral cavity of a user; The system, wherein the in vivo stimulus is light acting on an optogenetic target.

3. The system of claim 1 or 2, wherein at least a portion of the system is implantable.

4. The system of any one of claims 1 to 3, wherein the oral appliance comprises a plurality of delivery sites for delivering the stimulus from the stimulus source to the at least one ion channel.

5. The system of claim 4 , wherein the oral appliance includes a roof portion that can provide an additional or alternative delivery site.

6. The system according to any one of claims 1 to 5, wherein the intraoral appliance is an orthodontic retainer or an orthodontic plate.

7. The system of any of claims 1 to 5, wherein the oral appliance further comprises a wire loop or a removable fastening mechanism for retaining the oral appliance in the user's mouth.

8. The light is one of red, amber, blue, or green light; The system of any of claims 1 to 7, wherein the ion channels can be activated or deactivated by any one or more of red, amber, blue or green light.

9. 9. The system of claim 1, further comprising a control means configured to selectively deliver a control stimulus to said at least one ion channel for selective in vivo activation or deactivation of said at least one ion channel.

10. The system of any one of claims 1 to 9, wherein the at least one ion channel is formed only at at least one location selected for muscle cell stimulation.

11. The system of any one of claims 1 to 9, wherein the stimulus is delivered only to ion channels formed at at least one location selected for muscle cell stimulation.

12. at least one sensor that monitors at least one predetermined process aspect of a user; 12. The system of claim 1, wherein the at least one predetermined processing condition is selected from a user's respiratory cycle, breathing, respiratory cessation, apnea, hypopnea, diaphragmatic movement, muscle cell activity, neuronal activity, transthoracic impedance, thoracic movement, abdominal movement, airway pressure, temperature, pharyngeal narrowing, or pharyngeal collapse.

13. A system according to any preceding claim, wherein the system is suitable for use as a treatment for obstructive sleep apnea.

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