Neuromodulation systems, devices, and methods for alleviating symptoms associated with sinonasal inflammatory disease and related disorders

Abstract

The invention provides systems, devices, and methods for alleviating symptoms associated with a condition in a sinonasal cavity of a patient, such as sinonasal inflammatory disease, wherein such symptoms may include nasal congestion, facial pain and pressure, rhinorrhea and post-nasal drip. A neuromodulation device of the present invention includes a wearable or implantable oral appliance having one or more energy delivering elements strategically positioned along a surface thereof for delivery of therapeutic energy. The one or more energy delivering elements are positioned such that, upon the appliance being worn or implanted, the energy delivering elements become aligned with, and able deliver energy to, one or more target sites within the patient's oral cavity to thereby provide targeted stimulation of specific nerves to thereby alleviate symptoms.

Description

[0001] Attorney Docket No.: SINU-OOt / OlWO 40798 / 3

[0002] NEUROMODULATION SYSTEMS, DEVICES, AND METHODS FOR ALLEVIATING SYMPTOMS ASSOCIATED WITH SINONASAL INFLAMMATORY DISEASE AND

[0003] RELATED DISORDERS

[0004] Cross-Reference to Related Application(s)

[0005] This application is an international PCT application which claims priority to, and the benefit of, U.S. Provisional Application No. 63 / 705,150, filed October 9, 2024, the content of which is incorporated by reference herein in its entirety.

[0006] Technical Field

[0007] The disclosure relates to neuromodulation systems, methods, and devices for treating sinonasal inflammatory disease and related conditions by regulating autonomic tone through stimulation of oral and sinonasal neural pathways.

[0008] Background

[0009] Sinonasal inflammatory disease is an umbrella term that encompasses various conditions characterized by inflammation of the sinonasal mucous membranes. These conditions include allergic rhinitis (AR), non-allergic rhinitis (NAR), chronic rhinosinusitis (CRS), acute rhinosinusitis, recurrent acute rhinosinusitis and medication-resistant rhinitis. Symptoms of sinonasal inflammatory disease include, but are not limited to, nasal congestion / obstruction (i.e., the feeling that one is unable to breathe), nasal discharge (e.g., rhinorrhea or posterior nasal drip), facial pain, facial pressure, and reduced or loss of smell. While varying in severity, each condition within the sinonasal inflammatory disease spectrum presents challenges in management, especially when traditional medications fail. CRS for example, is a particularly burdensome condition within sinonasal inflammatory disease, characterized by persistent symptoms lasting more than 12 weeks. It significantly impacts quality of life and often leads to the need for surgical interventions when medications fail. CRS can cause severe headaches, chronic fatigue, sleep disturbances, and impair focus or motivation in daily activities.

[0010] Sinonasal inflammatory disease develops through a combination of physiological irregularities in the sinus and / or nasal cavities. It is well-established that one of the fundamental pillars of the disease is immune-mediated inflammation. Traditionally, this immune Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 dysregulation has been considered the primary driver of the disease. This dysregulated immune activity results in the overproduction of inflammatory mediators, which cause mucosal swelling, increased mucus production, and obstruction of normal mucosal flow. In the case of CRS specifically, this can result in bacteria and other contaminants becoming trapped in the sinonasal cavity, triggering an even greater immune response to manage the bacterial overgrowth. This vicious cycle of inflammation and mucus stasis exacerbates symptoms such as facial pain, pressure, impaired sense of smell, nasal congestion and discharge. The prolonged immune activity in the nasal tissues not only perpetuates inflammation but also leads to chronic tissue remodeling and persistent symptoms, significantly impacting the patient's quality of life.

[0011] In addition to immunological factors, emerging evidence shows that neural dysfunction may also contribute significantly to the pathophysiology of sinonasal inflammatory disease. The autonomic nervous system exists as a scale between sympathetic and parasympathetic activity. As one increases, the other must proportionately decrease in activity to regulate end-organ tissue. In the case of sinonasal inflammatory diseases such as CRS and rhinitis, disproportionate activation of the parasympathetic system with relative decreased action of the sympathetic system can lead to increased glandular secretion, vascular permeability, and mucosal edema, resulting in symptoms like nasal congestion, rhinorrhea and post-nasal drip. As a result, invasive procedures such as vidian neurectomy and posterior nasal nerve ablation are being employed to target overactive parasympathetic pathways in these patients.

[0012] The current standard of care for treatment of the vast majority of sinonasal inflammatory diseases largely focuses on the overactive immune system. The first line of therapy provided to patients diagnosed with one of these conditions is intranasal corticosteroids (INCS), in the form of sprays or large volume steroid rinses. INCS acts to down-regulate the immune response in the sinonasal cavity. Essentially, these steroids treat the tissue inflammation by targeting the immune response triggered by bacterial overgrowth or allergen exposure in the sinonasal cavity. But these topical treatments oftentimes do not reach all parts of the sinonasal cavity due to its large surface area or have a long-lasting effect due to limited contact time with the tissue, and improper patient rinsing / spraying technique. Therefore, patients consistently using nasal steroids only feel temporary relief of their symptoms, requiring multiple repetitive rinses / sprays during the day. Long-term use can also lead to side effects such as nasal irritation, dryness, nosebleeds, and even glaucoma due to elevated intraocular pressure. When symptoms persist despite regular use, Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 patients are left with limited alternatives. The patients that don’t improve with nasal steroids may then require additional procedures, such as functional endoscopic sinus surgery (FESS), septoplasty and inferior turbinate reduction and / or balloon sinuplasty. These procedures are not curative. Rather, such procedures involve surgical resection of tissue in the sinonasal cavity or enlarging the sinuses and nasal passages to provide larger paths for drug delivery to all parts of the nasal cavity. Therefore, even after these procedures, patients must continue the medical treatment with steroids. Most sinonasal inflammatory diseases require the patient to chronically use nasal steroids lifelong to avoid exacerbations and symptom recurrence.

[0013] To target the neural component of sinonasal inflammatory disease, surgical procedures, such as vidian neurectomy and posterior nasal nerve ablation / neurectomy, which aim to reduce parasympathetic overactivity, have shown efficacy in reducing symptoms such as rhinorrhea, post-nasal drip and nasal congestion particularly in chronic rhinitis. However, these interventions carry significant risks and complications due to the nonspecific site of autonomic denervation. Vidian neurectomy involves resecting the vidian nerve near critical vasculature and nerves, with a significant risk of irreversible complications such as dry eye, significant bleeding and potential vision loss. Similarly, the lack of precision with posterior nasal nerve ablation increases the risk of symptom recurrence from remaining intact parasympathetic nerves in the anatomic region.

[0014] Recent advancements in neuromodulation have explored alternative approaches for treating sinonasal inflammatory disease by modulating autonomic nerves through electrical stimulation. As a well-accepted form of technology, nerve stimulators and neuromodulation are supported by evidence demonstrating their ability to improve symptoms and address an aspect of the disease pathology currently being undertreated.

[0015] Summary

[0016] The invention of the present disclosure addresses the limitations of current sinonasal inflammatory disease medical and surgical interventions by providing a uniquely designed neuromodulation device configured to provide targeted and non-invasive modulation of autonomic pathways involved in the symptoms associated with sinonasal inflammatory disease. More specifically, the neuromodulation device is designed based on an understanding of the detailed anatomy and physiology of the nerves involved in sinonasal inflammatory disease, Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 including their synaptic interactions and autonomic regulation, as well the highly variable pathways of such nerves and associated structures within the nasal and oral cavities.

[0017] In certain embodiments, the device is in the form of a wearable, oral appliance. In other embodiments, the device is implantable. The device incorporates one or more energy delivering elements strategically positioned along a surface thereof and configured to deliver therapeutic energy to one or more target sites. In some embodiments, the energy delivering elements may be electrodes configured to deliver electrical pulses. In other embodiments, the energy delivering elements may include vibratory transducers configured to deliver vibratory energy in the form of mechanical vibrations. The energy delivering elements are positioned such that, upon the device being worn by a patient, or implanted within the patient’s oral cavity, the energy delivering elements are generally aligned with, and able deliver energy to, one or more target sites within the patient’s oral cavity, such as along the hard palate and / or soft palate of the patient’s oral cavity, to thereby provide targeted stimulation of specific nerves associated with such target sites. Stimulation at these sites modulates autonomic tone and mucous gland activity, resulting in reduced mucosal blood flow and mucous secretion, decreased nasal resistance, and improved airflow. Such physiological effects alleviate the symptoms of sinonasal inflammatory disease, including nasal congestion, facial pain and pressure, post-nasal drip, and loss of smell, with therapeutic benefit that may extend for hours after stimulation has ceased. The device may operate in open- or closed-loop modes using optional sensors (e.g., airflow, pressure, impedance) to adapt stimulation for patient-specific anatomy and response.

[0018] The one or more energy delivering elements may generally be positioned so as to provide targeted and controlled stimulation of specific nerves, including, but not limited to, the nasopalatine nerve (NPN). For example, in certain embodiments, the appliance (being inserted into a patient’s mouth and fitted within) is configured such that one or more elements contact mucosa adjacent to, or generally associated with, the NPN at the incisive foramen .The device further comprises a control module (including, but not limited to, a pulse generator, a rechargeable power source, microcontroller, a user interface module and a control circuit) operably coupled to the one or more electrodes and configured to control energy delivery therefrom. Energy delivery may be provided primarily as electrical pulses — monophasic or multiphasic (e.g., biphasic, triphasic) — using any known waveform and within specific frequency and intensity ranges, to achieve optimal therapeutic effects. In alternative Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 embodiments, the energy-delivering elements may deliver vibratory, mechanical, acoustic, optical, or thermal stimulation to achieve neuromodulation of the targeted nerves.

[0019] In a preferred embodiment, the device targets the NPN, a mixed nerve with sensory and autonomic fibers, at the incisive foramen in the oral cavity. By applying specific pulse parameters such as frequency, pulse shape, and pulse width, the device modulates autonomic regulation of the nasal mucosa. This neural normalization reduces nasal blood flow, mucus production, and congestion, resulting in improved nasal airflow and breathing, as well as reduced facial pain and pressure.

[0020] Accordingly, the disclosed neuromodulation device represents a significant advancement over existing therapies, wherein such existing therapies primarily address inflammation and immune dysregulation but fail to address the underlying neural overstimulation contributing to sinonasal inflammatory disease symptoms. By targeting this aspect of the disease, the disclosed device introduces a novel therapeutic mechanism that expands the range of available treatment options, offering a drug free and non-invasive solution, engineered to provide immediate and lasting relief, with potential benefits over existing therapies. In addition, this approach may be applicable to a broader patient population, including those with overlapping symptomatology.

[0021] Brief Description of the Drawings

[0022] Features and advantages of the claimed subject matter will be apparent from the following detailed description of embodiments consistent therewith, which description should be considered with reference to the accompanying drawings.

[0023] FIG. 1 is a cut-away lateral view illustrating the anatomy of portions of a nasal cavity and oral cavity, including nerves associated with the autonomic pathways involved in sinonasal inflammatory disease.

[0024] FIG. 2 is a cut-away frontal view illustrating the anatomy of portions of a nasal cavity and oral cavity, including nerves associated with the autonomic pathways involved in sinonasal inflammatory disease.

[0025] FIG. 3 is an axial view of an oral cavity illustrating the NPN and associated incisive foramen. Attorney Docket No.: SINU-OOl / OIWO 40798 / 3

[0026] FIG. 4A is a perspective view of one exemplary embodiment of a wearable neuromodulation device consistent with the present disclosure, specifically illustrating a bipolar electrode configuration in a horizonal arrangement.

[0027] FIG. 4B is a perspective view of another exemplary embodiment of a wearable neuromodulation device consistent with the present disclosure, specifically illustrating a bipolar electrode configuration in a vertical arrangement.

[0028] FIG. 5A is a perspective view of another exemplary embodiment of a wearable neuromodulation device consistent with the present disclosure, specifically illustrating a monopolar electrode configuration.

[0029] FIG. 5B shows a patient wearing the device of FIG. 5 A and further including a second electrode placed outside of the oral cavity of the patient, such as being placed on a patient’s neck.

[0030] FIG. 6 is a perspective view of another exemplary embodiment of a wearable neuromodulation device consistent with the present disclosure, specifically illustrating an array of electrodes.

[0031] FIG. 7 is a side view of an exemplary embodiment of a wearable neuromodulation device consistent wi7h the present disclosure, illustrating the electronics module (i.e., for housing the various electronic components of the device, including a pulse generator, microcontroller, memory unit, user interface, wireless charging component, and power source, such as a rechargeable battery).

[0032] FIG. 8 is an axial view of an oral cavity showing placement of the wearable oral appliance neuromodulation device of FIG. 4A, illustrating the electronics module in greater detail as well as specifically illustrating placement of the bipolar electrode configuration in a horizontal arrangement relative to the incisive foramen and NPN.

[0033] FIG. 9 is an axial view of an oral cavity showing placement of the wearable neuromodulation device of FIG. 4B, illustrating the electronics module in greater detail as well as specifically illustrating placement of the bipolar electrode configuration in a vertical arrangement relative to the incisive foramen and NPN.

[0034] FIGS. 10A through 10F show various pulse shapes associated with electrical pulses delivered via the one or more electrodes of the wearable neuromodulation device consistent with Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 the present disclosure. FIGS. 10A, 10B, IOC, 1OD, 1OE, and 1 OF show rectangular, sinusoidal, trapezoidal, ramp, exponential, and delta pulse shapes, respectively.

[0035] FIG. 11 is an axial view of an oral cavity showing placement of the wearable oral appliance neuromodulation device of FIG. 6.

[0036] FIG. 12 is an axial view of an oral cavity showing placement of a wearable oral appliance neuromodulation device, which is similarly configured as the device illustrated in FIG. 4B.

[0037] FIGS. 13 and 14 illustrate other embodiments of oral appliance consistent with the present disclosure, generally in the form of a mouthguard structure adapted to conform to the upper dentition of a patient. The appliance of FIG. 13 includes a user-actuatable input comprising an on / off button, while the appliance of FIG. 14 does not include a user-actuatable input comprising an on / off button, but rather may be controlled, in part, via an external, wireless controller.

[0038] FIG. 15 illustrates an embodiment of a handheld remote controller configured to wirelessly operate the device of the present invention.

[0039] FIG. 16 is a flow diagram illustrating a method for alleviating symptoms associated with a condition within a sinonasal cavity of a patient consistent with the present disclosure, wherein the condition may include a sinonasal inflammatory disease.

[0040] For a thorough understanding of the present disclosure, reference should be made to the following detailed description, including the appended claims, in connection with the abovedescribed drawings. Although the present disclosure is described in connection with exemplary embodiments, the disclosure is not intended to be limited to the specific forms set forth herein. It is understood that various omissions and substitutions of equivalents are contemplated as circumstances may suggest or render expedient.

[0041] Detailed Description

[0042] By way of overview, the present invention is directed to a uniquely designed neuromodulation device configured to provide targeted and non-invasive therapeutic energy for the neuromodulation of autonomic pathways involved in sinonasal inflammatory disease. More specifically, the neuromodulation device is designed based on an understanding of the detailed anatomy and physiology of the nerves involved, including their synaptic interactions and Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 autonomic regulation, as well the highly variable pathways of such nerves and associated structures within the nasal and oral cavities.

[0043] As used herein, “neuromodulation” refers to altering neural activity (e.g., activating, inhibiting, stimulating, modulating, or regulating) in the central, peripheral, or autonomic nervous systems, including modulation of autonomic tone affecting mucosal blood flow and glandular secretion. “Therapeutic energy” includes electrical, mechanical / vibratory, acoustic, optical, thermal, or magnetic energy. “Configured to” indicates structure adapted or arranged to perform the recited function.

[0044] FIGS. 1, 2, and 3 provide various views of the nasal and oral cavity. In particular, FIG. 1 is a cut-away lateral view illustrating the anatomy of portions of a nasal cavity and oral cavity, including nerves associated with the autonomic pathways involved in sinonasal inflammatory disease. FIG. 2 is a cut-away frontal view illustrating the anatomy of portions of a nasal cavity and oral cavity, including nerves associated with the autonomic pathways involved in sinonasal inflammatory disease. FIG. 3 is an axial view of an oral cavity illustrating the NPN and associated incisive foramen.

[0045] As shown in FIGS. 1-3, the nasal cavity and paranasal sinuses are innervated by a network of nerves, including both parasympathetic and sympathetic fibers, which play a crucial role in the pathophysiology of sinonasal inflammatory disease. Sensory innervation to the sinonasal cavity primarily comes from branches of the trigeminal nerve (cranial nerve V), specifically the ophthalmic (VI) and maxillary (V2) divisions. Important nerves in this network include the maxillary nerve, anterior and posterior ethmoidal nerves, infraorbital nerve, and nasopalatine nerve (NPN). The anterior and posterior ethmoidal nerves, branches of the nasociliary nerve from the ophthalmic division (VI), innervates the anterior, middle and posterior ethmoidal air cells and the anterior septum, playing a key role in sensory perception of the nasal mucosa and often involved in sinusitis-related pain. The infraorbital nerve, a branch of the maxillary division (V2), provides sensory innervation to the maxillary sinus, upper teeth, and anterior face and upper lip, commonly linked to facial pain in CRS. The NPN, another branch of the maxillary division (V2), innervates the nasal septum and the anterior hard palate.

[0046] The autonomic nervous system, comprising sympathetic and parasympathetic fibers, regulates various functions of the nasal mucosa, such as vasodilation, mucus secretion, and inflammatory responses. Sympathetic fibers originate from the superior cervical ganglion and Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 travel along the internal carotid artery, reaching the nasal cavity via the deep petrosal nerve, which merges with the greater petrosal nerve to form the nerve of the pterygoid canal (vidian nerve). Sympathetic innervation primarily causes vasoconstriction and reduces mucus secretion, temporarily relieving nasal congestion. In contrast, parasympathetic fibers originate from the superior salivatory nucleus and travel via the facial nerve (cranial nerve VII), joining the greater petrosal nerve to form the nerve of the pterygoid canal. Parasympathetic innervation leads to vasodilation and increased mucus secretion, and overactivity of these fibers can exacerbate sinonasal inflammatory disease symptoms, such as nasal congestion and excessive mucus production.

[0047] Sympathetic neurotransmission involves the release of epinephrine / norepinephrine, which binds to adrenergic receptors, causing vasoconstriction. In contrast, parasympathetic neurotransmission involves the release of acetylcholine, which binds to muscarinic receptors, leading to vasodilation and increased glandular secretion. While immune-mediated inflammation has traditionally been viewed as the primary driver of sinonasal inflammatory disease, emerging evidence highlights the critical role of autonomic imbalance. Parasympathetic overactivity contributes to inflammation, excessive mucus production, and nasal congestion, while inadequate sympathetic activity fails to counterbalance these effects, suggesting that the neural component plays a significant role in disease progression.

[0048] To target the neural component of sinonasal inflammatory disease, surgical procedures, such as vidian neurectomy and posterior nasal nerve ablation / neurectomy, which aim to reduce parasympathetic overactivity, have shown efficacy in reducing symptoms such as rhinorrhea, post-nasal drip and nasal congestion particularly in chronic rhinitis. However, these interventions carry significant risks and complications due to the nonspecific site of autonomic denervation. Vidian neurectomy involves resecting the vidian nerve near critical vasculature and nerves, with known irreversible complications such as dry eye, significant bleeding and potential vision loss. Similarly, the lack of precision with posterior nasal nerve ablation opens the opportunity for symptom recurrence from remaining intact parasympathetic nerves in the anatomic region.

[0049] The drawbacks of such surgical interventions highlight the need for safer, less invasive treatments. Unlike surgical interventions, which often involve significant risks and complications, non-invasive devices can modulate the parasympathetic and sympathetic tone in the nasal mucosa without collateral damage. The interplay of autonomic fibers and their effects Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 on nasal physiology underscores the importance of nerve-targeted treatments in managing sinonasal inflammatory disease. Therefore, targeted neuromodulation therapies, such as electrical stimulation of specific nerves, offer promising treatment strategies. Nerve stimulators and neuromodulation are well-established technologies, supported by evidence demonstrating their effectiveness in improving symptoms and addressing a key aspect of the disease pathology currently undertreated.

[0050] Understanding the detailed anatomy and physiology of the nerves involved in sinonasal inflammatory disease, including their synaptic interactions and autonomic regulation, enables the development of new therapeutic approaches that provide more effective and sustained symptom relief. The NPN, a branch of the maxillary division (V2) of the trigeminal nerve, is a mixed nerve carrying both autonomic and sensory fibers, playing a significant role in the innervation of the nasal and palatal regions. The NPN emerges from the pterygopalatine ganglion (PPG) and traverses through the sphenopalatine foramen (SPF) into the nasal cavity. The SPF is located within the posterior region of the lateral nasal cavity, and its precise location can vary slightly among individuals. Typically, the SPF is situated in the middle meatus, but it can also be found in the superior meatus or at the junction of the superior and middle meatuses. This variability poses a challenge for surgical navigation and intervention.

[0051] The incisive foramen, through which the NPN passes, is located in the anterior part of the hard palate, just behind the upper central incisors. This foramen serves as a conduit for the nerve as it travels from the nasal cavity to the oral cavity. The position of the incisive foramen is generally consistent and easily accessible, making it a reliable target for therapeutic interventions aimed at the NPN.

[0052] From the incisive foramen, the NPN travels upwards and branches into several key nerves that contribute to the innervation of the nasal mucosa and palatal tissues. As the NPN ascends, it connects with the PPG, which also gives fibers to the greater palatine nerve and other relevant nerves such as the posterior nasal nerves. These branches are involved in transmitting sensory information and autonomic signals that regulate various functions of the nasal mucosa, including mucus secretion and blood flow.

[0053] The PPG, located in the pterygopalatine fossa (PPF), is a critical relay station for autonomic fibers. Parasympathetic fibers from the facial nerve synapse in the PPG before sending postganglionic fibers to the nasal mucosa via the NPN and other branches. This ganglion Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 also receives sympathetic fibers that pass through without synapsing, providing a route for both parasympathetic and sympathetic regulation of nasal functions.

[0054] Recent microanatomic studies have shown that the anatomy of the PPF and the pathways of the nerves exiting the PPG are highly variable. Efferent rami from the PPG project to the orbit and nasal mucosa through numerous small nerve fascicles, rather than a single postganglionic autonomic nerve. Studies indicate that a significant majority of humans (approximately 87%) have microforamina and micro rami in the palatine bone, creating a complex network of nerve pathways.

[0055] This variability underscores the need for a targeted and non-invasive approach to modulating the autonomic pathways involved in sinonasal inflammatory disease rather than direct ablation of a complex network of nerves.

[0056] The present invention leverages this anatomical knowledge to propose a neuromodulation device that provides precise and controlled stimulation of specific nerves to thereby alleviate symptoms of sinonasal inflammatory disease, such as nasal congestion, facial pain and pressure, post-nasal drip, and loss of smell. For example, in the embodiments described herein, the neuromodulation device of the present invention is generally in the form of a wearable, oral appliance, that includes one or more energy delivering elements (i.e., electrodes) strategically positioned along a surface thereof. The one or more electrodes are positioned such that, upon being worn by a patient, the electrodes are generally aligned with, and able deliver energy to, one or more target sites within the patient’s oral cavity (i.e., along the hard palate and / or soft palate of the patient’s oral cavity) to thereby provide targeted stimulation of specific nerves associated with such target sites to alleviate symptoms of sinonasal inflammatory disease.

[0057] The one or more electrodes may generally be positioned so as to provide targeted and controlled stimulation of specific nerves, including, but not limited to, the nasopalatine nerve (NPN). For example, upon being worn by the patient (the oral appliance being inserted into a patient’s mouth and fitted within), the one or more electrodes are strategically placed to contact mucosa adjacent to, or generally associated with, the NPN at the incisive foramen. The wearable device comprises a control module (including, but not limited to, a pulse generator, a rechargeable power source, a user interface module and a control circuit) operably coupled to the one or more electrodes and configured to control energy delivery therefrom. The wearable device is configured to deliver electrical pulses, via the one or more electrodes, to the targeted nerve(s), Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 including the NPN. Such electrical pulses may be single phase (monophasic) or multiphase (e.g., biphasic, triphasic, etc.) and have any known waveforms, within specific frequency and intensity ranges, so as to achieve optimal therapeutic effects. By targeting the NPN, specifically at the incisive foramen within a patient’s oral cavity, the device can effectively influence the autonomic pathways of the nasal mucosa by normalizing neural input, thereby reducing inflammation, mucus production, and nasal congestion for improved airflow and breathing in nasal passageways.

[0058] Accordingly, the wearable neuromodulation device represents a significant advancement over existing therapies, which primarily focus on managing inflammation and immune dysregulation but fail to address the neural overstimulation contributing to sinonasal inflammatory disease symptoms. The novel neuromodulation device of the present invention offers a non-pharmaceutical, minimally invasive solution for sinonasal inflammatory disease patients who may or may not have responded to traditional medical management. The primary patient benefits include reduced mucus production, decreased post-nasal drip, decreased nasal congestion, and overall improvement in patient-reported outcomes. Importantly, due to its mechanism of action, the wearable neuromodulation device of the present invention has the potential to benefit a wider population suffering from the aforementioned symptoms, whether caused by chronic or acute conditions.

[0059] It should be noted that, while the present disclosure generally describes the device of the present invention as a wearable, oral appliance, other embodiments may include an implantable version of the device, in which the neuromodulation device can be implanted within a patient’s oral cavity and provide the intended treatment.

[0060] It should further be noted that the neuromodulation device described herein is configured to target a division or branch of the maxillary division of the trigeminal nerve, wherein said division or branch selected from the group consisting of greater palatine, lesser palatine, anterior nasal nerve, posterior nasal nerve, lateral nasal nerve, anterior ethmoidal nerve, posterior ethmoidal nerve, pterygopalatine ganglion, zygomatic nerve, nasociliary nerve, infraorbital nerve, pharyngeal nerve, vidian nerve; and nasopalatine nerve. As such, while the following description discusses use of the oral appliance for targeting the NPN at the incisive foramen within the oral cavity, the device is not limited to stimulation of the NPN and can be used for stimulation / neuromodulation of other nerves, as described herein. Attorney Docket No.: SINU-OOl / OIWO 40798 / 3

[0061] As described herein, the neuromodulation device of the present invention is generally in the form of an oral appliance configured to be positioned within a patient’s oral cavity. The device includes one or more electrodes provided on a surface of the oral appliance and configured to contact tissue at one or more respective target sites within the oral cavity upon positioning of the housing within the oral cavity. Each of the one or more electrodes is configured to deliver electrical pulses to targeted neural tissue at, or associated with, the one or more respective target sites within the oral cavity, wherein the targeted neural tissue is associated with autonomic pathways involved in sinonasal inflammatory disease, and wherein the delivery of electrical pulses is at a level and for a time period sufficient to therapeutically modulate the targeted neural tissue to thereby reduce symptoms of sinonasal inflammatory disease.

[0062] In some embodiments, the oral appliance may be configured to position electrodes near the incisive foramen or other palatal target sites using a variety of approaches. While thermoforming over a dental mold is one option, other methods may be employed. For example, electrodes can be embedded directly into the appliance material during fabrication, attached on the surface using adhesives or wraps that conform to the teeth, or integrated into flexible circuits or printed structures. Additive manufacturing techniques, such as 3D printing with conductive pathways, or deposition of conductive materials onto the appliance surface, may also be used to achieve precise geometries. In certain embodiments, the appliance may be self-molded by the patient, using thermoplastic or other conformable materials that adapt to the dentition and hard palate arch during fitting, thereby eliminating the need for a pre-fabricated dental mold. In certain embodiments, electrodes may be incorporated into removable films or strips that adhere to the palate or dentition, providing replaceable or single-use formats. Hybrid methods can also be used, combining embedded structures with surface-mounted or printed elements.

[0063] FIGS. 4A and 4B show a bipolar electrode configuration, while FIG. 5A shows a monopolar electrode configuration. Referring to FIG. 4A, one exemplary embodiment of the device is illustrated showing a bipolar electrode configuration in a horizonal arrangement (i.e., side-to-side arrangement across a surface of the device), while FIG. 4B shows another embodiment of the device having a bipolar electrode configuration in a vertical arrangement (i.e., front-to-back arrangement across a surface of the device). In each embodiment, the device includes two electrodes positioned on a surface of the device that contacts a portion of a patient’s palate when the patient is wearing the oral appliance, thereby positioning the electrodes into Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 engagement with a respective target site associated with a branch or division of the maxillary division of the trigeminal nerve, such as the nasopalatine nerve (NPN).

[0064] FIG. 5A shows another exemplary embodiment of the device having a monopolar electrode configuration, in which a single electrode is positioned on a surface of the device that contacts a portion of a patient’s palate when the patient is wearing the oral appliance. In the monopolar configuration, a second electrode is placed outside of the oral cavity of the patient, such as being placed on a patient’s neck, as shown in FIG. 5B.

[0065] As will be described in greater detail herein, the electrodes of each embodiment (i.e., the two electrodes in the bipolar configuration and the single electrode in the monopolar configuration) are configured to make contact with mucosa adjacent to, or generally associated with, a branch or division of the maxillary division of the trigeminal nerve. For example, as shown in FIGS. 8 and 9, the electrodes are configured to make contact with mucosa adjacent to, or generally associated with, the nasopalatine nerve (NPN) at an incisive foramen within the oral cavity.

[0066] It should be noted that the electrodes may also be configured as an array (as shown in FIGS. 6 and 11), allowing for selective activation of individual electrodes or groups of electrodes to optimize nerve targeting and accommodate anatomical variability. FIG. 6 is a perspective view of another exemplary embodiment of a wearable neuromodulation device consistent with the present disclosure, specifically illustrating an array of electrodes.

[0067] FIG. 7 is a side view of an exemplary embodiment of the wearable neuromodulation device, in the form of an oral appliance, illustrating placement of an electronics module relative to the electrodes. FIG. 8 is an axial view of an oral cavity showing placement of the wearable neuromodulation device of FIG. 4A, illustrating the electronics module in greater detail as well as specifically illustrating placement of the bipolar electrode configuration in a horizontal arrangement relative to the incisive foramen and NPN. FIG. 9 is an axial view of an oral cavity showing placement of the wearable neuromodulation device of FIG. 4B, illustrating the electronics module in greater detail as well as specifically illustrating placement of the bipolar electrode configuration in a vertical arrangement relative to the incisive foramen and NPN.

[0068] The electronics module is operably coupled to the one or more electrodes and configured to generate and control delivery of electrical pulses from the one or more electrodes. In particular, as shown, the electronics module may generally include: a pulse generator for Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 generating electrical pulses; a control circuit (also referred to herein as a microcontroller) for modulating and adjusting parameters of the electrical pulses and generally controlling transmission of electrical signals from the pulse generator to the electrodes; a rechargeable power source (i.e., a rechargeable battery) for energizing the device and from which electrical pulses are generated; a memory unit for storing data related to at least use of the device; a charging port (wired or wireless) for charging the battery and a user interface module including input interface and communication circuitry configured to receive user commands from a physical control (e.g., an on / off button) and / or an external controller (e.g., a handheld remote, smartphone, or computing device), and to transmit corresponding control signals to the control circuit. The user interface module may further enable bi-directional data communication between the device and an external system. In some embodiments, the device may include a physical on / off control located on the electronics module itself. In other embodiments, operation of the device, including activation, deactivation, and adjustment of stimulation intensity, may be controlled remotely via an external controller (e.g., a handheld remote, smartphone, or computing device) that communicates with the user interface module through wired or wireless communication (e.g., Bluetooth, NFC, or RF). In certain embodiments, both a physical on / off control and a remote control interface may be provided, allowing complementary user control of the device. The device may further include a sensor configured to measure feedback including at least one physiological parameter of the patient during use of the device such as, for example, a patients nasal airflow, nasal resistance, mucosal tissue swelling, heart rate, and blood oxygen saturation.

[0069] In some embodiments, tissue impedance is sampled using an electrode mesh across the palatal surface to generate a placement map that differentiates between mucosa, periosteum, and neural structures. A control circuit, which may include a microcontroller, analyzes the impedance data by comparing the measured values to stored reference profiles to identify the target region. Based on this analysis, the system can automatically activate the subset of electrodes or vibratory transducers within an array that are proximal to the identified nerve, thereby directing therapeutic energy precisely to the desired neural tissue without requiring manual adjustment. The microcontroller serves as the central device’s “brain”, controlling pulse generator parameters — including frequency, amplitude, pulse width, and duty cycle — and may dynamically adjust them in response to feedback signals such as real-time impedance Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 measurements or other sensor inputs, in a closed-loop manner. Tn addition, the microcontroller monitors the electrode-tissue interface, adjusts the applied voltage to achieve the desired current amplitude, and modulates the stimulation dose according to user preferences or pre-programmed treatment protocols. The microcontroller may also store usage data, facilitate communication with external devices (e g., smartphones), and implement safety features such as overcurrent protection.

[0070] The pulse generator is generally responsible for producing electrical pulses. It is powered by the battery and is in electrical communication with the electrodes. The electrical pulses can be monophasic or biphasic and comprise a waveform shape selected from the group consisting of sinusoidal, square, rectangular, triangular, delta, trapezoidal, sawtooth, exponential, and any custom waveform. In particular, biphasic pulses are characterized by a positive phase followed by a negative phase, ensuring charge balance and minimizing the risk of tissue damage or electrode polarization. The pulse generator may incorporate electronic components such as capacitors, resistors, transistors, and integrated circuits to shape and regulate the output waveform, providing precise control over stimulation parameters and ensuring consistent delivery of therapeutic pulses.

[0071] The rechargeable battery provides the necessary power for the device operation. The battery may be lithium-ion or another suitable type, selected for its energy density, longevity, and safety profile. The device may also include a charging port or wireless charging capabilities for convenient recharging.

[0072] The electrodes, which may be made of biocompatible materials such as stainless steel, platinum-iridium, or conductive polymers, are designed to interface with the NPN at the incisive foramen. The electrode shape and configuration may vary, with options for a single electrode, multiple electrodes in a linear or matrix array, or other arrangements that optimize nerve stimulation. The positioning of the electrodes may be customized for each patient to account for anatomical variability, thereby ensuring accurate targeting of the target nerve and consistent therapeutic efficacy. The electrodes may be replaceable to ensure hygiene and longevity. The preferred configuration includes bipolar configuration, with two distinct electrodes positioned laterally to the incisive foramen (i.e., the horizontal configuration of FIG. 4A), or posteriorly and anteriorly (i.e., the vertical configuration of FIG. 4B). However, as previously described, the electrodes may include a monopolar configuration (see FIGS. 5A and 5B), with a first electrode Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 positioned at the incisive foramen and a second electrode positioned outside of the oral cavity at the head or neck area, possibly the back of the neck or the ear of the patient.

[0073] It should be noted that the device may be charged by a case that not only stores the oral appliance but also contains a built-in battery that can recharge the oral appliance when not in use.

[0074] FIGS. 10A through 10F show various pulse shapes associated with electrical pulses delivered via the one or more electrodes of the wearable neuromodulation device consistent with the present disclosure. FIGS. 10A, 10B, IOC, 10D, 10E, and 10F show rectangular, sinusoidal, trapezoidal, ramp, exponential, and delta pulse shapes, respectively.

[0075] FIG. 11 is an axial view of an oral cavity showing placement of the wearable oral appliance neuromodulation device of FIG. 6. The appliance is shown as a mouthguard structure adapted to conform to the upper dentition of a patient. One or more electrodes are positioned along the palatal surface in proximity to the incisive foramen to enable targeted stimulation of the nasopalatine nerve. The appliance further houses or is operably connected to an electronics module which may include a battery, pulse generator, electrodes aligned with corresponding openings in the appliance, and control circuitry for regulating stimulation parameters, as well as an input interface and communication circuitry configured to receive user commands from a physical control (e.g., an on / off button) and / or an external controller (e.g., a handheld remote, smartphone, or computing device). In some embodiments, the appliance is custom-molded to patient dentition, while in other embodiments it may be self-molded, adhesively secured, or otherwise adapted for intraoral retention.

[0076] FIG. 12 is an axial view of an oral cavity showing placement of a wearable oral appliance neuromodulation device, which is similarly configured as the device illustrated in FIG. 4B. As shown, the appliance is shown as a mouthguard structure adapted to conform to the upper dentition of a patient. One or more electrodes are positioned along the palatal surface in proximity to the incisive foramen to enable targeted stimulation of the nasopalatine nerve. The appliance further houses or is operably connected to an electronics module which may include a battery, pulse generator, input interface and communication circuitry configured to receive user commands from a physical control (e.g., an on / off button) and / or an external controller (e.g., a handheld remote, smartphone, or computing device), electrodes aligned with corresponding openings in the appliance, and control circuitry for regulating stimulation parameters. In some embodiments, the appliance is custom -molded to patient dentition, while in other embodiments it Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 may be self-molded, adhesively secured, or otherwise adapted for intraoral retention. In this embodiment, the device further includes a user-actuatable input that may be used for controlling operation of the electronics module to thereby control operation of the device, the user-actuatable input comprising an on / off button.

[0077] FIGS. 13 and 14 illustrate other embodiments of oral appliance consistent with the present disclosure, generally in the form of a mouthguard structure adapted to conform to the upper dentition of a patient. The appliance of FIG. 13 includes a user-actuatable input comprising an on / off button, while the appliance of FIG. 14 does not include a user-actuatable input comprising an on / off button, but rather may be controlled, in part, via an external, wireless controller. As shown, one or more electrodes are positioned along the palatal surface in proximity to the incisive foramen to enable targeted stimulation of the nasopalatine nerve. The appliance further houses or is operably connected to an electronics module which may include a battery, pulse generator, electrodes aligned with corresponding openings in the appliance, and control circuitry for regulating stimulation parameters and an input interface and communication circuitry configured to receive user commands from a physical control (e.g., an on / off button) and / or an external controller (e.g., a handheld remote, smartphone, or computing device). In some embodiments, the appliance is custom-molded to patient dentition, while in other embodiments it may be self-molded, adhesively secured, or otherwise adapted for intraoral use.

[0078] FIG. 15 illustrates an embodiment of a handheld remote controller configured to wirelessly operate the device of the present invention. The controller includes an ON / OFF button and light indicator positioned near the top surface of the device, configured to activate or deactivate the neuromodulation system and to provide visual feedback regarding device status. The controller further includes a pair of intensity control buttons (+ / -) configured to increase or decrease the stimulation intensity or other operating parameters of the neuromodulation device. In some embodiments, the remote controller communicates wirelessly with the electronics module of the intraoral device via Bluetooth, RF, or other wireless communication protocols to transmit control commands or receive status data.

[0079] FIG. 16 is a flow diagram illustrating a method for alleviating symptoms associated with a condition within a sinonasal cavity of a patient consistent with the present disclosure, wherein the condition may include a sinonasal inflammatory disease. As previously described herein, the method may include delivering a neuromodulation signal at or near an oral or palatal target site, Attorney Docket No.: SINU-001 / 01WO 40798 / 3 such as the incisive foramen, to stimulate neural pathways including the nasopalatine nerve and / or greater palatine nerve. Stimulation of these nerves modulates autonomic tone within the nasal mucosa by altering sympathetic and parasympathetic activity. This modulation reduces nasal blood flow and glandular secretion, thereby improving airflow and relieving symptoms such as congestion, facial pain and pressure, post-nasal drip, and rhinorrhea.

[0080] As previously described herein, the neuromodulation device delivers electrical pulses to the NPN at the incisive foramen, modulating neural activity and influencing the neural pathways involved in sinonasal inflammatory disease pathogenesis. The specific stimulation parameters, including frequency, pulse width, and amplitude, may be adjustable to accommodate individual patient needs and treatment protocols.

[0081] Stimulation at the NPN elicits a response by sending an electric signal along its fibers to the pterygopalatine ganglion. The signal travels through the NPN, which carries sensory and autonomic fibers, to the pterygopalatine ganglion located in the pterygopalatine fossa. Within the ganglion, the signal modulates the parasympathetic postganglionic neurons and stimulates sympathetic neurons. These neurons then project fibers that join branches of the maxillary nerve (V2), such as the posterior, superior and inferior lateral nasal nerves, and the greater and lesser palatine nerve. These fibers innervate the nasal mucosa and glands, where they regulate autonomic functions. By influencing these pathways, the stimulation can increase sympathetic activity and reduce parasympathetic activity. The resulting release of sympathetic neurotransmitters such as norepinephrine promotes vasoconstriction and reduces glandular secretion, thereby alleviating symptoms of sinonasal inflammatory disease, including nasal congestion, facial pain, mucus production, post-nasal drip, and rhinorrhea.

[0082] Some pre-clinical and clinical studies have shown promising results with biphasic pulses at stimulation frequencies ranging from 10-40 Hz, pulse widths of 100-300 microseconds, and amplitudes of 0.2-lmA, adjusted to achieve therapeutic effect without discomfort. In these studies, a rapid and long-lasting (hours) decongestion effect with improved nasal airflow was observed following a single short stimulation treatment time of 5 minutes. Two electrodes were placed in a bipolar configuration, laterally to the NPN. The optimal stimulation parameters may vary depending on individual patient characteristics and the severity of symptoms, but we have consistently observed effective results within the specified ranges. The device may incorporate algorithms or user interfaces to facilitate personalized dose titration. Attorney Docket No.: SINU-OOl / OIWO 40798 / 3

[0083] The present invention offers several advantages over existing neuromodulation devices and treatment modalities for rhinitis and chronic rhinosinusitis.

[0084] The device of the present invention is the first to offer non-invasive regulation of hyperactive nasal nerves, a key player in the neural pathways involved in sinonasal inflammatory disease pathogenesis. This targeted approach allows for effective neuromodulation and potential downregulation of hyperactive nasal nerves without the need for invasive procedures like vidian neurectomy, sphenopalatine ganglion block, and posterior nasal nerve ablation / neurectomy.

[0085] To target the neural component of sinonasal inflammatory disease, surgical procedures, such as vidian neurectomy and posterior nasal nerve ablation / neurectomy, which aim to reduce parasympathetic overactivity, have shown efficacy in reducing symptoms such as rhinorrhea, post-nasal drip and nasal congestion particularly in chronic rhinitis. However, these interventions carry significant risks and complications due to the nonspecific site of autonomic denervation. Vidian neurectomy involves resecting the vidian nerve near critical vasculature and nerves, with a significant risk of irreversible complications such as dry eye, significant bleeding and potential vision loss. Similarly, the lack of precision with posterior nasal nerve ablation opens the opportunity for symptom recurrence from remaining intact parasympathetic nerves in the anatomic region.

[0086] The device of the present invention circumvents these issues by providing a precise and non-invasive method to target the neural pathways responsible for sinonasal inflammatory disease. By avoiding the need for invasive procedures, it reduces the risk of complications and allows for adjustable and repeatable treatments. This innovation represents a significant advancement in the management of sinonasal inflammatory disease, offering patients a safer and more effective alternative to surgical approaches.

[0087] The oral appliance form factor offers a comfortable and discreet wearable solution, enabling convenient and consistent treatment throughout the day. The oral appliance form factor offers a comfortable and discreet wearable solution, enabling convenient and consistent treatment throughout the day. With a discreet design and proven efficacy, levels of compliance greatly increase. This expectation is supported by the success seen with other wearable oral cavity devices which have achieved good compliance rates due to their user-friendly and unobtrusive nature. This suggests that the device of the present invention, designed with similar principles of comfort and convenience, will encourage patients to adhere to their treatment Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 regimen, ultimately leading to better outcomes in the management of sinonasal inflammatory disease.

[0088] In addition to the wearable design, an implantable version of the device is contemplated. This implantable design aims to provide a more permanent and compliant solution for patients. The implantable version would incorporate the same core components and functionalities as the wearable device, with additional considerations for biocompatibility and surgical placement. The inclusion of this design in the draft of claims reflects our commitment to offering versatile treatment options that cater to varying patient needs and preferences.

[0089] The device further allows for adjustable stimulation parameters, and treatment regimen (stimulation time) enabling personalized treatment plans tailored to individual patient needs and responses.

[0090] The device offers a non-pharmaceutical alternative for patients who have not responded to traditional medical management, reducing the reliance on medications and their potential side effects.

[0091] While the present invention demonstrates significant potential in alleviating sinonasal inflammatory disease symptoms, further research and development are ongoing. Future iterations of the device may incorporate additional features such as: biofeedback mechanisms (i.e., integration of biofeedback sensors (e.g., nasal airflow sensors, pressure sensors) could enable real-time monitoring of treatment response and automatic adjustment of stimulation parameters; connectivity and data logging (i.e., wireless connectivity to smartphones or other devices could facilitate data logging, remote monitoring, and personalized treatment recommendations; and expanded indications (i.e., the device's mechanism of action suggests potential applications across a range of conditions characterized by nasal congestion, including allergic rhinitis, non- allergic rhinitis, chronic rhinosinusitis, acute rhinosinusitis, recurrent acute rhinosinusitis and medication-resistant rhinitis.

[0092] The present invention represents a groundbreaking advancement in the field of neuromodulation for sinonasal inflammatory disease treatment, by directly addressing the neural component of the pathophysiology. Its unique design, targeted stimulation approach, and personalized therapy capabilities offer the potential to significantly improve the quality of life for millions of individuals suffering from this debilitating condition. Attorney Docket No.: SINU-OOl / OIWO 40798 / 3

[0093] As used in any embodiment herein, the term “module” may refer to software, firmware and / or circuitry configured to perform any of the aforementioned operations. Software may be embodied as a software package, code, instructions, instruction sets and / or data recorded on non- transitory computer readable storage medium. Firmware may be embodied as code, instructions or instruction sets and / or data that are hard-coded (e.g., nonvolatile) in memory devices. “Circuitry”, as used in any embodiment herein, may comprise, for example, singly or in any combination, hardwired circuitry, programmable circuitry such as computer processors comprising one or more individual instruction processing cores, state machine circuitry, and / or firmware that stores instructions executed by programmable circuitry. The modules may, collectively or individually, be embodied as circuitry that forms part of a larger system, for example, an integrated circuit (IC), system on-chip (SoC), desktop computers, laptop computers, tablet computers, servers, smartphones, etc.

[0094] Any of the operations described herein may be implemented in a system that includes one or more storage mediums having stored thereon, individually or in combination, instructions that when executed by one or more processors perform the methods. Here, the processor may include, for example, a server CPU, a mobile device CPU, and / or other programmable circuitry.

[0095] Also, it is intended that operations described herein may be distributed across a plurality of physical devices, such as processing structures at more than one different physical location. The storage medium may include any type of tangible medium, for example, any type of disk including hard disks, floppy disks, optical disks, compact disk read-only memories (CD-ROMs), compact disk rewritables (CD-RWs), and magneto-optical disks, semiconductor devices such as read-only memories (ROMs), random access memories (RAMs) such as dynamic and static RAMs, erasable programmable read-only memories (EPROMs), electrically erasable programmable read-only memories (EEPROMs), flash memories, Solid State Disks (SSDs), magnetic or optical cards, or any type of media suitable for storing electronic instructions. Other embodiments may be implemented as software modules executed by a programmable control device. The storage medium may be non-transitory.

[0096] As described herein, various embodiments may be implemented using hardware elements, software elements, or any combination thereof. Examples of hardware elements may include processors, microprocessors, circuits, circuit elements (e.g., transistors, resistors, capacitors, inductors, and so forth), integrated circuits, application specific integrated circuits Attorney Docket No.: SINU-OOl / OIWO 40798 / 3

[0097] (ASIC), programmable logic devices (PLD), digital signal processors (DSP), field programmable gate array (FPGA), logic gates, registers, semiconductor device, chips, microchips, chip sets, and so forth.

[0098] 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. Thus, 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, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0099] The terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention, in the use of such terms and expressions, of excluding any equivalents of the features shown and described (or portions thereof), and it is recognized that various modifications are possible within the scope of the claims. Accordingly, the claims are intended to cover all such equivalents.

[0100] Incorporation by Reference

[0101] References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes.

[0102] Equivalents

[0103] Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.

Claims

Attorney Docket No.: SINU-OOl / OIWO 40798 / 3Claims1. A neuromodulation device for alleviating symptoms associated with a condition within a sinonasal cavity of a patient, the device comprising: a housing in the form of an oral appliance or oral implant configured to be positioned or implanted, respectively, within a patient’s oral cavity; and one or more energy delivering elements provided on a surface of the housing and configured to contact tissue at one or more respective target sites within the oral cavity upon positioning of the housing within the oral cavity, wherein each of the one or more energy delivering elements is configured to deliver therapeutic energy to targeted neural tissue at, or associated with, the one or more respective target sites within the oral cavity, wherein the targeted neural tissue is associated with autonomic pathways involved with symptoms of the condition, and wherein the delivery of therapeutic energy is at a level and for a time period sufficient to therapeutically modulate the targeted neural tissue to thereby reduce symptoms associated with the condition.

2. The neuromodulation device of claim 1, wherein the therapeutic energy is selected from the group consisting of electrical energy and vibratory energy.

3. The neuromodulation device of claim 2, wherein the one or more energy delivering elements comprise one or more electrodes, and wherein the therapeutic energy comprises electrical pulses.

4. The neuromodulation device of claim 3, wherein the one or more electrodes are provided in a bipolar configuration or a monopolar configuration.

5. The neuromodulation device of claim 4, wherein, in a bipolar configuration, the device comprises two electrodes spaced apart from one another and provided on a surface of the housing such that the two electrodes contact tissue at respective locations within the oral cavity.

6. The neuromodulation device of claim 4, wherein, in a monopolar configuration, the device comprises a first electrode provided on a surface of the housing such that the first electrodeAttorney Docket No.: SINU-OOl / OIWO 40798 / 3 contacts tissue at a response location within the oral cavity and a second electrode positioned outside of the oral cavity and configured to contact tissue on the patient’s head or neck area.

7. The neuromodulation device of claim 3, wherein the one or more electrodes are formed from a biocompatible material selected from the group consisting of stainless steel, silver, platinumiridium, titanium, gold, and conductive polymers.

8. The neuromodulation device of claim 3, wherein the electrical pulses are monophasic or biphasic and comprise a waveform shape selected from the group consisting of sinusoidal, square, rectangular, triangular, delta, trapezoidal, sawtooth, exponential, and any custom waveform.

9. The neuromodulation device of claim 3, wherein the one or more electrodes are configured to contact tissue at one or more respective target sites within the oral cavity and deliver electrical pulses to a division or branch of the maxillary division of the trigeminal nerve, said division or branch selected from the group consisting of greater palatine, lesser palatine, anterior nasal nerve, posterior nasal nerve, lateral nasal nerve, pterygopalatine ganglion, zygomatic nerve, nasociliary nerve, infraorbital nerve, anterior ethmoidal nerve, posterior ethmoidal nerve, pharyngeal nerve, vidian nerve; and nasopalatine nerve.

10. The neuromodulation device of claim 2, wherein the one or more energy delivering elements comprise one or more vibratory transducers, and wherein the therapeutic energy comprises mechanical vibrations.

11. The neuromodulation device of claim 1, wherein the housing comprises a wearable, oral appliance and wherein the one or more energy delivering elements are positioned along a surface of the housing that contacts a portion of a patient’s palate when the patient is wearing the oral appliance.Attorney Docket No.: SINU-OOl / OIWO 40798 / 312. The neuromodulation device of claim 11, wherein the one or more energy delivering elements are configured to make contact with mucosa adjacent to, or generally associated with, a branch or division of the maxillary division of the trigeminal nerve.

13. The neuromodulation device of claim 12, wherein the one or more energy delivering elements are configured to make contact with mucosa adjacent to, or generally associated with, the nasopalatine nerve (NPN) at the incisive foramen within the oral cavity.

14. The neuromodulation device of claim 11, wherein the wearable, oral appliance can be custom-fitted or non-custom fitted to the patient’s maxillary dentition.

15. The neuromodulation device of claim 14, wherein the wearable, oral appliance structure is custom-fitted or self-molded via a method selected from the group consisting of thermoforming, three-dimensional (3D) printing, and dental impression molding of thermoplastic or other conformable materials that adapt to individual dentition.

16. The neuromodulation device of claim 1, wherein the housing comprises an implantable structure designed to be placed within the oral cavity and engage tissue adjacent to, or near, the nasal cavity and / or the maxillary division of the trigeminal nerve.

17. The neuromodulation device of claim 1, further comprising an electronics module operably coupled to the one or more energy delivering elements and configured to generate and control delivery of therapeutic energy from the one or more energy delivering elements.

18. The neuromodulation device of claim 17, wherein the one or more energy delivering elements comprise one or more electrodes, and wherein the therapeutic energy comprises electrical pulses.

19. The neuromodulation device of claim 18, wherein the electronics module comprises: a pulse generator for generating electrical pulses;Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 a control circuit for modulating and adjusting parameters of the electrical pulses, said parameters selected from the group consisting of frequency, pulse width, pulse shape, and amplitude, wherein the control circuit is further configurable to adjust the parameters; a power source for energizing the device and from which electrical pulses are generated; and a microcontroller for controlling input of pulses to the electrodes; and a user interface module comprising input interface circuitry and communication circuitry configured to receive user commands from a physical control disposed on the device and / or from an external controller, and to transmit corresponding control signals to the control circuit.

20. The neuromodulation device of claim 19, wherein the power source is a rechargeable battery or a battery with a predetermined limited lifespan.

21. The neuromodulation device of claim 17, wherein the one or more energy delivering elements comprise one or more vibratory transducers, and wherein the therapeutic energy comprises vibratory energy in the form of mechanical vibrations.

22. The neuromodulation device of claim 21, wherein the electronics module comprises: a control circuit for adjusting parameters of the vibratory energy, said parameters selected from the group consisting of frequency and amplitude, wherein the control circuit is further configurable to adjust the parameters; a a power source for energizing the device and from which vibratory energy is generated; and a microcontroller for controlling input to the vibratory transducers.

23. The neuromodulation device of claim 22, wherein the power source is a rechargeable battery or a battery with a limited lifespan.

24. The neuromodulation device of claim 17, wherein the electronics module comprises a user- actuatable input for controlling operation of the electronics module, the user-actuatable input comprising an on / off button.Attorney Docket No.: SINU-OOl / OIWO 40798 / 325. The neuromodulation device of claim 17, further comprising a memory unit for storing data related to the use of the device.

26. The neuromodulation device of claim 17, further comprising a sensor configured to measure feedback including at least one physiological parameter of the patient during use of the device.

27. The neuromodulation device of claim 26, wherein the control circuit is configured to adjust delivery of therapeutic energy from the one or more energy delivering elements based, at least in part, on feedback from the sensor.

28. The neuromodulation device of claim 27, wherein at least one physiological parameter is selected from the group consisting of nasal airflow, nasal resistance, mucosal tissue swelling, heart rate, and blood oxygen saturation.

29. The neuromodulation device of claim 1, wherein the effect of stimulation can be elicited from targeted neural tissue at a distance greater than 4 cm away from the target sites.

30. The neuromodulation device of claim 1, wherein the condition is sinonasal inflammatory disease and the symptoms are selected from the group consisting of nasal congestion, facial pain, facial pressure, post-nasal drip, rhinorrhea and loss of smell.

31. The neuromodulation device of claim 1, further comprising a sensor configured to measure a tissue impedance value at the one or more respective target sites.

32. The neuromodulation device of claim 31, further comprising a control circuit operably coupled to the sensor, wherein the control circuit is configured to identify a location of the targeted neural tissue based, at least in part, on the measured tissue impedance value.

33. A method for alleviating symptoms associated with a condition within a sinonasal cavity of a patient, the method comprising:Attomey Docket No.: SINU-OOl / OIWO 40798 / 3 positioning or implanting a neuromodulation device within an oral cavity of a patient, the neuromodulation device comprising: a housing in the form of an oral appliance or an implant; and one or more energy delivering elements provided on a surface of the housing and configured to contact tissue at or near one or more respective target sites within the oral cavity upon positioning or implantation of the housing within the oral cavity; and delivering, via the one or more energy delivering elements, therapeutic energy to targeted neural tissue at, or associated with, the one or more respective target sites within the oral cavity, wherein the targeted neural tissue is associated with autonomic pathways involved with symptoms of the condition, and wherein the delivery of therapeutic energy is at a level and for a time period sufficient to therapeutically modulate the targeted neural tissue to thereby reduce symptoms associated with the condition.

34. The method of claim 33, wherein the therapeutic energy is selected from the group consisting of electrical energy and vibratory energy, and wherein the one or more energy delivering elements comprise one or more electrodes for delivering electrical pulses and / or one or more vibratory transducers for delivering mechanical vibrations.

35. The method of claim 34, wherein the one or more electrodes are provided in a bipolar configuration or a monopolar configuration.

36. The method of claim 35, wherein, in a bipolar configuration, the device comprises two electrodes spaced apart from one another and provided on a surface of the housing such that the two electrodes contact tissue at respective locations within the oral cavity.

37. The method of claim 35, wherein, in a monopolar configuration, the device comprises a first electrode provided on a surface of the housing such that the first electrode contacts tissue at a response location within the oral cavity and a second electrode positioned outside of the oral cavity and configured to contact tissue on the patient’s head or neck area.

38. The method of claim 34, wherein the one or more electrodes are formed from a biocompatible material selected from the group consisting of stainless steel, silver, platinum-Attorney Docket No.: SINU-001 / 01WO 40798 / 3 iridium, titanium, gold, and conductive polymers.

39. The method of claim 34, wherein the electrical pulses are monophasic or biphasic and comprise a waveform shape selected from the group consisting of sinusoidal, square, rectangular, triangular, delta, trapezoidal, sawtooth, exponential, and any custom waveform.

40. The method of claim 34, wherein the one or more electrodes are configured to contact tissue at one or more respective target sites within the oral cavity and deliver electrical pulses to a division or branch of the maxillary division of the trigeminal nerve, said division or branch selected from the group consisting of greater palatine, lesser palatine, anterior nasal nerve, posterior nasal nerve, lateral nasal nerve, pterygopalatine ganglion, zygomatic nerve, nasociliary nerve, infraorbital nerve, pharyngeal nerve, vidian nerve; and nasopalatine nerve.

41. The method of claim 34, wherein each electrical pulses comprises: a frequency ranging from about 0.1 Hz to about 2000 Hz; a pulse width ranging from about 1 microseconds to about 10,000 microseconds; and pulse amplitude ranging from about 0 mA to about 5 mA.

42. The method of claim 34, wherein the delivery of electrical pulses causes a reduction in mucous gland mucin production, causes arterial vasoconstriction, and causes a reduction in venodilation in the sinonasal cavity through direct stimulation of the targeted neural tissue and the release of sympathetic neurotransmitters selected from the group consisting of norepinephrine, epinephrine, and neuropeptide Y and further causes inhibition of parasympathetic neurotransmitters such as acetylcholine.

43. The method of claim 33, wherein the device further comprises an electronics module operably coupled to the one or more electrodes and configured to generate and control delivery of electrical pulses from the one or more electrodes, the electronics module comprising: a pulse generator for generating electrical pulses;Attorney Docket No.: SINU-OOl / OIWO 40798 / 3 a control circuit for modulating and adjusting parameters of the electrical pulses, said parameters selected from the group consisting of frequency, pulse width, pulse shape, and amplitude, wherein the control circuit is further configurable to adjust the parameters; a power source for energizing the device and from which electrical pulses are generated; a microcontroller for controlling input of pulses to the electrodes; and a memory unit for storing data related to at least use of the device; and a user interface module comprising input interface circuitry and communication circuitry configured to receive user commands from a physical control disposed on the device and / or from an external controller, and to transmit corresponding control signals to the control circuit.

44. The method of claim 43, wherein, prior to, or during, the step of delivering, via the one or more energy delivering elements, therapeutic energy to targeted neural tissue, the method comprises: activating the pulse generator of the device to generate electrical pulses; configuring the parameters of the electrical pulses using the control circuit of the device; storing data related to the use of the device in the memory unit; and measuring at least one physiological parameter of the patient using a sensor of the device and adjusting at least one of the frequency, pulse width, and amplitude of a given electrical pulse based, at least in part, on the measured physiological parameter.

45. The method of claim 44, wherein the at least one physiological parameter is selected from the group consisting of nasal airflow, nasal resistance, mucosal tissue swelling, heart rate, and blood oxygen saturation.

46. The method of claim 43, wherein the power source is a rechargeable battery or a battery with a predetermined limited lifespan.

47. The method of claim 43, wherein the electronics module comprises a user-actuatable input for controlling operation of the electronics module, the user-actuatable input comprising an on / off button.Attorney Docket No.: SINU-OOl / OIWO 40798 / 348. The method of claim 33, wherein the housing of the neuromodulation device comprises a wearable, oral appliance structure and wherein the one or more energy delivering elements are positioned along a surface of the housing that contacts a portion of a patient’s palate when the patient is wearing the oral appliance.

49. The method of claim 48, wherein the one or more energy delivering elements are configured to make contact with mucosa adjacent to, or generally associated with, a branch or division of the maxillary division of the trigeminal nerve.

50. The method of claim 49, wherein the one or more energy delivering elements are configured to make contact with mucosa adjacent to, or generally associated with, the nasopalatine nerve (NPN) at the incisive foramen within the oral cavity.

51. The method of claim 48, wherein the wearable, oral appliance structure is custom-fitted or non-custom fitted to the patient’s maxillary dentition.

52. The method of claim 51, wherein the wearable, oral appliance structure is custom-fitted or self-molded via a method selected from the group consisting of thermoforming, three- dimensional (3D) printing, and dental impression molding of thermoplastic or other conformable materials that adapt to individual dentition.

53. The method of claim 33, wherein the housing comprises an implantable structure designed to be placed within the oral cavity and engage tissue adjacent to, or near, the nasal cavity and / or the maxillary division of the trigeminal nerve.

54. The method of claim 33, wherein the effect of stimulation can be elicited from targeted neural tissue at a distance greater than 4 cm away from the target site.

55. The method of claim 33, wherein the condition is sinonasal inflammatory disease and the symptoms are selected from the group consisting of nasal congestion, facial pain, rhinorrhea, facial pressure and post-nasal drip.Attorney Docket No.: SINU-OOl / OIWO 40798 / 356. The method of claim 33, further comprising, prior to the step of delivering therapeutic energy: measuring a tissue impedance value at the one or more respective target sites using a sensor coupled to the housing; and identifying a location of the targeted neural tissue based on the measured tissue impedance value.

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