Methods to regenerate upper airway and digestive tract tissues with microenergy acoustic pulse or low-intensity pulsed ultrasound

Abstract

Devices, systems, software, and methods are provided for treating sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorders with microenergy acoustic pulse (MAP) stimulation. MAP stimulation of muscles of the upper aerodigestive tract increases muscle mass and contractility strength, increases the proportion of fast-twitch muscle fibers, reduces numbers of senescent cells, and activates muscle stem cells to regenerate muscle tissue.

Description

METHODS TO REGENERATE UPPER AIRWAY AND DIGESTIVE TRACT TISSUES WITH MICROENERGY ACOUSTIC PULSE OR LOW-INTENSITY PULSED ULTRASOUNDCROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims benefit under 35 U.S.C. § 119(e) of provisional application 63 / 756,518, filed February 10, 2025, which application is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] The upper aerodigestive tract is a musculomucosal unit composed of several distinct but interactive anatomical sites that are critical to safe swallows, effortless voicings, and unlabored respirations. Myogenous structural and functional integrity of the tongue, pharynx, and larynx is necessary for sustaining optimal performance. The tongue is a multifunctional organ vital for food intake, food bolus preparation and transit, and patency of the upper airway. Extrinsic tongue and laryngeal muscles exert dynamic control over upper airway configuration, pulling the tongue forward and averting airway luminal collapse, the sine qua non clinical finding in obstructive sleep apnea. The pharynx is essential to moving the food bolus prepared in the oral cavity for safe and effective transit into the lower digestive tract. The pharyngeal muscle sling acts in sequential constriction and relaxation rhythm to propel the food bolus through the upper esophageal sphincter. In parallel, extrinsic and intrinsic laryngeal muscles act in coordination to prevent the food bolus from entering and contaminating the lower tracheobronchial airway. Beyond safe swallows, the larynx is central to voice production, self-identification, and emotional expression. Laryngeal muscles fine tune vocal fold tension for natural vocal projection, sustained vocal intensity, and uninterrupted mellifluous vocal quality. Impairment of upper aerodigestive tract functional integrity mediated by age-related sarcopenia contributes to oropharyngeal dysphagia, aspiration pneumonia, and presbyphonia, and obstructive sleep apnea-related ineffective or inadequate myogenous action worsens breathing pauses and daytime sleepiness.

[0003] Oropharyngeal dysphagia (OD) is ineffective delivery of the food bolus from the oral cavity to the esophagus (Cooket al. (1999) Gastroenterology 116(2):455-478). This condition may arise from or be exacerbated by neuromuscular dysfunction at distinct upper aerodigestive tract sites. Tongue and oral cavity muscles involved with food bolus preparation or propulsion, and pharyngeal and laryngeal coordinated muscle activity to move the bolus from the pharynx to the upper esophageal sphincter are two identifiable sites of deglutition where dysfunction contributes to OD (Schindler et al. (2002) Swallowing disorders in the elderly. Laryngoscope 112(4):589-602). Within the fastestgrowing segment of adults, aged 65 or older, OD prevalence is between 10-30% (Barczi et al. (2000) Semin Speech Lang. 21(4):347-61; Lin et al. (2002) J Am Geriatr Soc. 50(6): 1118-23) and is much higher in frail and institutionalized older adults (Cabre et al. (2010) Age Ageing 39(1):39-45; Carrion et al. (2015) Clin Nutr. 34(3):436-442; Clave et al. (2015) Nat Rev Gastroenterol. Hepatol. 12(5):259- 270). Clinical consequences of insufficient alimentation are dehydration and malnutrition, perpetuating a cycle of frailty and institutionalization (Clave et al., supra; Baijens et al. (2016) Clin Interv Aging 11:1403-1428; Ortega et al. (2014) Age Ageing 43(1): 132-137; Rofes et al. (2011) Gastroenterol Res Pract 2011:818979). Beyond swallowing, OD may be complicated by inadequate safeguarding of the upper airway from food stream contamination of the tracheobronchial tree, leading to aspiration pneumonia (Almirall et al. (2012) Nestle Nutr Inst Workshop Ser. 72:67-76; Marik et al. (2003) Chest. 124(1):328-336; Ortega et al. (2024) Semin Respir Crit Care Med.45(6):678-693). Sarcopenia of the upper aerodigestive tract as a causative factor of OD is supported by associations with reduced skeletal muscle mass (Maeda et al. (2017) J Gerontol A Biol Sci Med Sci. 72(9): 1290-1294; Wakabayashi et al. (2014) J Frailty Aging 3(2):97-103) and tongue pressure and jaw-opening force (Machida et al. (2017) Geriatr Gerontol Int. 17(2):295-301). Imaging studies on older adults have reported tongue (Tamura et al. (2012) Dysphagia 27 (4): 556-561) and geniohyoid muscle atrophy, 26 tongue muscle fatty replacement4 and pharyngeal muscle volume reduction (Aminpour et al. (2011) Ear Nose Throat J. 90(4):E1; Molfenter et al. (2015) Dysphagia.30(3):321-327). Treatments for oropharyngeal dysphagia center on functional optimization of the oral and pharyngeal swallowing phases. Food texture modification to soften consistencies and thicken fluids (Azzolino et al. (2019) Aging Clin Exp Res. 31 (6): 799-805; National Dysphagia Diet Task Force., American Dietetic Association. National dysphagia diet: standardization for optimal care. Chicago, III: American Dietetic Association; 2002. vii, 47 pages; Ney et al. (2009) Nutr Clin Pract.24(3):395-413; Sura et al. (2012) Clin Interv Aging. 7:287-298) and swallowing muscle strength and resistance training (Baijens et al., supra; Burkhead et al. (2007) Dysphagia 22(3):251-65; Wakabayashi et al. (2018) Nutrition. 48:111-6), and swallowing exercises (Farsi et al. (2024) Dysphagia Epub 20241202) mitigate sarcopenia-related dysfunction. Medications that cloud the sensorium are reassessed and enteral feeding tubes that bypass the upper aerodigestive tract are sometimes used to maintain nutritional status or mitigate aspiration pneumonia risk. Transcutaneous electrical stimulation for other classes of dysphagia has yielded mixed outcomes. Its use as an adjunctive modality to other rehabilitative techniques is recommended (Barikroo et al. (2020) Rehabil Res Pract. 2020:4865614. Epub 20200511, PMCID: PMC7238355)

[0004] Age-related changes of the larynx in older adults can degrade voicing function, referred to as presbyphonia. Clinical manifestations include early vocal fatigue, reduced vocal projection orintensity, tremulous or unstable vocal output, and frank hoarseness (Gregory et al. (2012) J Voice.26(2):254-258; Martins et al. (2014) Aging Clin Exp Res. 26(1): 1 -5). Videolaryngoscopy documents bowing of vocal fold free edges with incomplete glottic closure due to vocalis muscle atrophy or vocalis sarcopenia (Santos et al. (2023) Eur. Arch. Otorhinolaryngol. 280(2)781-788; Martins et al., supra Kendall (2007) CurrOpin Otolaryngol Head NeckSurg. 15(3):137-140; Kost et al. (2018) Clin Geriatr Med. 34(2): 191 -203). Videostroboscopy shows abnormal vibratory properties of the vocal folds (Martins et al., supra), where alterations in vocal fold viscoelastic properties may be related to changes in collagen and elastin support of the lamina propria (Butler et al. (2001) Laryngoscope.111 (5):907-911 ; Long (2018) Laryngoscope 128(1): 153-159; Sato et al. (2002) Ann. OtoL Rhinol. Laryngol. 111(1):15-20).40-42).

[0005] The prevalence of voice disorders of adults aged 65 or older is between 20-30% (Golub et al. (2006) J Am Geriatr Soc. 54(11): 1736-1739; Roy et al. (2007) Laryngoscope 117(4):628-633; Saccente-Kennedy et al. (2024) J Voice, 2024 Jan 8:S0892-1997(23)00396-X; Wong et al. (2020) Am. J. Otolaryngol. 41 (2): 102367). Noninvasive behavioral and exercise treatment for presbyphonia improves auditory-perceptual outcome in controlled studies (Bhatt et al. (2023) Laryngoscope.133(11):2846-2855; et al. (2019) J Voice. 33(5):809 e19- e26) Invasive treatment to restore loss of vocal fold tissue volume as a consequence of sarcopenia by injection laryngoplasty (Kelly et al. (2021) J Voice. 35(5)789-792; Kwon et al. (2010) Laryngoscope 120(2):326-329; Pinto et al. (2007) Otolaryngol Head Neck Surg. 137(5)785-791) and laryngeal framework surgery (Allensworth et al. (2019) J Voice. 33(1):40-44; Isshiki et al. (1996) Ann Otol Rhinol Laryngol. 105(3): 182-188; van den Broek et al. (2020) Eur Arch Otorhinolaryngol. 277(7):2023-9. Epub 20200402) 53-55 report favorable short-term voice outcomes.

[0006] Myogenic dysfunction-based obstructive sleep apnea (OSA) is associated with genioglossus muscle inadequacy to dilate the upper airway lumen (Oliven et al. (2020) Respir Physiol Neurobiol.274:103362, Epub 20191219; Mezzanotte et al. (1992) J Clin Invest. 89(5): 1571-1579) and lateral pharyngeal wall collapse (Edwards (2011) Head Neck 33 Suppl 1 (Suppl 1):S37-45; Patil et al. (2007) J Appl Physiol (1985) 102(2): 547-556, Epub 20060928; Vroegop et al. (2014) Laryngoscope.124(3)797-802, Epub 20131211) during sleep. OSA symptoms include breathing disturbance manifested by snoring and respiratory pauses, and excessive daytime somnolence (Chang et al. (2023) International Consensus Statement on Obstructive Sleep Apnea, Int Forum Allergy Rhinol.13(7): 1061-482; Malhotra et al. (2018) J Clin Sleep Med. 14(7): 1245-1247, Epub 20180715). OSA prevalence is 14% in men and 5%in women, where the rate increases with obesity (Chang et al, supra). Neuromodulation treatment of moderate-to-severe OSA by hypoglossal nerve stimulation targeting the genioglossus muscle to effect greater contractility dilates the upper airway by pullingthe tongue forward (Chang et al, supra), but it is ineffective to prevent lateral pharyngeal wall collapse (Vroegop AV, Vanderveken OM, Boudewyns AN, Scholman J, Saldien V, Wouters K, Braem MJ, Van de Heyning et al. (2014) Laryngoscope 124(3): 797-802; Huyett et al. (2021) Laryngoscope.131 (7): 1676-1682; Qi et al. (2024) Eur Arch OtorhinolaryngoL 281(7):3333-3343). Ansa cervicalis stimulation targeting the sternothyroid muscles combined with hypoglossal nerve stimulation increases airway dilation benefit (Kent et al. (2021) J Appl Physiol 131(2):487-95).

[0007] With aging (Bureau USC. U.S. Older Population Grew From 2010 to 2020 at Fastest Rate Since 1880 to 1890 2023. Available from: census. gov / library / stories / 2023 / 05 / 2020-census-united- states-older-population-grew.html) and obstructive sleep apnea (Chang et al., supra) prevalence on the rise, sarcopenia-related (tongue, geniohyoid, pharynx, larynx) upper aerodigestive tract disorders (Molfenter et aL, supra Nakao et al. (2021) Dysphagia 36(3):483-491; Santos et aL, supra), and myogenic dysfunction-based (genioglossus, pharynx) obstructive sleep apnea conditions (Edwards et aL, supra; Oliven et aL, supra; Patil et aL, supra) are expected to grow in significance. There remains a need to develop methods to regenerate and strengthen the upper aerodigestive tract muscles to treat broad classes of swallowing, voicing, and breathing disorders.SUMMARY OF THE INVENTION

[0008] Devices, systems, software, and methods are provided for treating sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorders with microenergy acoustic pulse (MAP) stimulation. MAP stimulation of muscles of the upper aerodigestive tract increases muscle mass and contractility strength, increases the proportion of fast-twitch muscle fibers, reduces numbers of senescent cells, and activates muscle stem cells to regenerate muscle tissue.

[0009] In one aspect, a method of treating a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder in a subject is provided, the method comprising administering MAP stimulation to an upper aerodigestive tract muscle of the subject.

[0010] In certain embodiments, the sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder is dysphagia, presbyphonia, a breathing disorder, aspiration pneumonia, or obstructive sleep apnea.

[0011] In certain embodiments, the sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder involves geniohyoid muscle atrophy, tongue muscle fatty replacement, pharyngeal muscle volume reduction, vocalis muscle atrophy, or genioglossus muscle atrophy.

[0012] In certain embodiments, the upper aerodigestive tract muscle is a tongue muscle, an oral cavity muscle, a pharyngeal muscle, or a laryngeal muscle.

[0013] In certain embodiments, the tongue muscle is a genioglossus muscle, a hyoglossus muscle, a styloglossus muscle, a palatoglossus muscle, a superior longitudinal lingual muscle, an inferior longitudinal lingual muscle, a transverse lingual muscle, or a vertical lingual muscle. In some embodiments, the laryngeal muscle is a thyroarytenoid muscle, a vocalis muscle, a lateral cricoarytenoid muscle, a posterior cricoarytenoid muscle, an interarytenoid muscle, a suprahyoid muscle, or an infrahyoid muscle. In some embodiments, the suprahyoid muscle is a digastric muscle, a stylohyoid muscle, a mylohyoid muscle, or a geniohyoid muscle. In some embodiments, the infrahyoid muscle is a sternohyoid muscle, a sternothyroid muscle, a thyrohyoid muscle, or omohyoid muscle. In some embodiments, the pharyngeal muscle is a superior pharyngeal constrictor muscle, a middle pharyngeal constrictor muscle, an inferior pharyngeal constrictor muscle, a palatopharyngeus muscle, a salpingopharyngeus muscle, or a stylopharyngeus muscle. In some embodiments, the oral cavity muscle is a bilateral mylohyoid muscle, a buccinator muscle, or a geniohyoid muscle.

[0014] In certain embodiments, the administering of the MAP stimulation increases muscle contractility strength, increases muscle mass, or increases proportion of fast-twitch muscle fibers of the upper aerodigestive tract muscle compared to in absence of the administering the MAP stimulation.

[0015] In certain embodiments, the administering of the MAP stimulation decreases numbers of senescent cells in the upper aerodigestive tract muscle.

[0016] In certain embodiments, the administering of the MAP stimulation increases tongue pressure or jaw-opening force compared to in absence of said administering the MAP stimulation.

[0017] In certain embodiments, the MAP stimulation is administered to a genioglossus muscle and a laryngeal muscle for treatment of obstructive sleep apnea.

[0018] In certain embodiments, the MAP stimulation is administered to a pharyngeal muscle for treatment of dysphagia.

[0019] In certain embodiments, the MAP stimulation is administered to a laryngeal muscle for treatment of dysphonia.

[0020] In certain embodiments, the subject is elderly, bedridden, in intensive care, or has a broken limb.

[0021] In certain embodiments, the MAP stimulation is administered using a shockwave probe. In some embodiments, the method further comprises positioning the shockwave probe at a location on the neck of the subject to deliver the MAP stimulation to the muscle of the upper aerodigestive tract. In some embodiments, the shockwave probe is a focused shockwave probe or a radial shockwave probe.

[0022] In certain embodiments, the MAP stimulation is administered with an energy flux density of 0.033 mJ / mm2to 0.05 mJ / mm2.

[0023] In certain embodiments, multiple cycles of MAP stimulation are administered to the subject.In some embodiments, the MAP stimulation is administered daily or intermittently. In some embodiments, the MAP stimulation is administered two or three times a week.

[0024] In another aspect, a method of maintaining or increasing muscle mass or contractility strength of an upper aerodigestive tract muscle is provided, the method comprising administering MAP stimulation to the upper aerodigestive tract muscle.

[0025] In another aspect, a method of regenerating an upper aerodigestive tract tissue is provided, the method comprising administering MAP stimulation to the upper aerodigestive tract tissue.

[0026] In another aspect, a method of activating endogenous stem cells to regenerate muscle tissue in an upper aerodigestive tract muscle of a subject is provided, the method comprising administering microenergy acoustic pulse (MAP) stimulation to the upper aerodigestive tract muscle.

[0027] In another aspect, a system for performing MAP therapy is provided, the system comprising:a MAP generator; a shockwave probe operatively coupled to the MAP generator, wherein the shockwave probe is adapted for positioning at a location to deliver MAP stimulation to a muscle of the upper aerodigestive tract of a subject; and a processor programmed to instruct the shockwave probe to deliver MAP stimulation to the upper aerodigestive tract of the subject using the shockwave probe in a manner effective to treat a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder in the subject.

[0028] In certain embodiments, the shockwave probe is adapted for positioning at a location to deliver MAP stimulation to a genioglossus muscle and a laryngeal muscle fortreatment of obstructive sleep apnea.

[0029] In certain embodiments, the shockwave probe is adapted for positioning at a location to deliver MAP stimulation to a pharyngeal muscle for treatment of dysphagia.

[0030] In certain embodiments, the shockwave probe is adapted for positioning at a location to deliver MAP stimulation to a laryngeal muscle for treatment of dysphonia.

[0031] In certain embodiments, the shockwave probe is adapted for positioning on the neck of a subject.

[0032] In certain embodiments, the shockwave probe is a focused shockwave probe or a radial shockwave probe.

[0033] In certain embodiments, the system further comprises a user interface comprising an input electronically coupled to the processor for instructing the shockwave probe to deliver MAP stimulation to the subject to treat the sarcopenia-related or myogenic dysfunction-based upperaerodigestive tract disorder. In some embodiments, the user interface is password protected and is operable by a health care practitioner. In some embodiments, the user interface is configured to receive input from the health care practitioner for one or more parameters of the MAP stimulation, wherein the one or more parameters are selected from a target region of the upper aerodigestive tract, stimulation duration, number of pulses, pulse length, pulse frequency, energy flux density, and pressure amplitude.

[0034] In certain embodiments, the system further comprises a storage component for storing data, wherein the storage component is coupled to the processor.

[0035] In certain embodiments, the system further comprises a display for displaying information about the MAP therapy.

[0036] In certain embodiments, the display further displays a user interface presenting a questionnaire configured to receive input from the subject regarding self-reported results of treatment with the MAP stimulation.

[0037] In certain embodiments, the display further displays a user interface to allow modification of the MAP therapy by the user, wherein the user can change a stimulation pulse pattern or spatial geometry of the MAP stimulation.BRIEF DESCRIPTION OF THE DRAWINGS

[0038] FIGS. 1A-1C. (FIG. 1A) Schematic of experimental workflow. (FIG. 1B) Anterior neck muscle groups. (FIG. 1C) Position of MAP probe on the anterior neck with pulses directed at muscles of the upper aerodigestive tract.

[0039] FIG. 2. Cross-sectional Area and Minimum Feret Diameter Muscle Measurements. Myofibers of MAP stimulated animals have larger transverse cross-sectional area and larger minimum Feret diameter, indicating muscle regeneration by hypertrophy or hyperplasia.

[0040] FIG. 3. Ex Vivo Myobath Fatigability. MAP stimulation alters sternohyoid muscle fatigability profile, suggesting a differential strengthening effect favoring fast myofibers. The mean Fatigue Index [FI=(Finitial- Ffinal) / Finitial X100] and mean time difference between Finitial and 50% of Finitial (Time- 50) are computed. The data show the Fatigue Index is increased by the MAP stimulation, while Time- 50 is not significantly different, suggesting MAP-stimulated animals increased fast myofibers.

[0041] FIGS.4A-4C Senescence-Associated ^-Galactosidase Activity. The tongue and sternohyoid muscles of MAP-stimulated animals have lower senescent cell counts. (FIG. 4A) Histology of senescent cells (X-gal +) in tongue (transverse / vertical, superior longitudinal), sternohyoid, and genioglossus muscles (Control vs MAP stimulated). (FIG. 4B) MAP stimulated cohort has fewer senescent cells (X-gal +) in the tongue (*P<0.001) and sternohyoid (*P<0.05) muscles. (FIG. 4C)Both transverse vertical and superior longitudinal muscle types of the tongue in MAP stimulated animals have fewer senescent cells (X-gal +) (*p < 0.05).DETAILED DESCRIPTION OF THE INVENTION

[0042] Devices, systems, software, and methods are provided for treating sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorders with microenergy acoustic pulse stimulation. MAP stimulation of muscles of the upper aerodigestive tract increases muscle mass and contractility strength, increases the proportion of fast-twitch muscle fibers, reduces numbers of senescent cells, and activates muscle stem cells to regenerate muscle tissue.

[0043] Before the present devices, systems, software, and methods are described, it is to be understood that this invention is not limited to the particular devices, systems, software, and methods described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0044] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0045] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, some potential and preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited. It is understood that the present disclosure supersedes any disclosure of an incorporated publication to the extent there is a contradiction.

[0046] As will be apparent to those of skill in the art upon reading this disclosure, each of the individual embodiments described and illustrated herein has discrete components and features which may be readily separated from or combined with the features of any of the other severalembodiments without departing from the scope or spirit of the present invention. Any recited method can be carried out in the order of events recited or in any other order which is logically possible.

[0047] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a muscle" includes a plurality of such muscles and reference to "the probe" includes reference to one or more probes, and so forth.

[0048] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.Definitions

[0049] The term "about," particularly in reference to a given quantity, is meant to encompass deviations of plus or minus five percent.

[0050] The term “sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder” is used herein to refer to a condition or disease associated with loss of muscle mass, contractility strength, and / or function of one or more muscles of the upper aerodigestive tract, which may include, without limitation, muscles of the tongue (e.g., genioglossus, hyoglossus, styloglossus, palatoglossus, superior longitudinal, inferior longitudinal, transverse, and vertical lingual muscles), oral cavity (e.g., bilateral mylohyoid muscles, buccinator muscle, geniohyoid muscles), throat (e.g., pharyngeal muscles such as the constrictor muscles, including the superior pharyngeal constrictor, middle pharyngeal constrictor, and inferior pharyngeal constrictor muscles; and the elevator muscles, including the palatopharyngeus, salpingopharyngeus, and stylopharyngeus muscles), voice box (e.g., laryngeal muscles such as the thyroarytenoid muscle, vocalis muscle, lateral cricoarytenoid muscle, posterior cricoarytenoid muscle, interarytenoid muscle, suprahyoid muscles, including digastric, stylohyoid, mylohyoid, and geniohyoid muscles; infrahyoid muscles, including sternohyoid, sternothyroid, thyrohyoid, omohyoid muscles), esophagus (e.g., esophageal striated skeletal muscles such as in the upper third of the esophagus, smooth muscles such as in the middle and lower thirds of the esophagus, the upper esophageal sphincter, and the lower esophageal sphincter), and soft palate (e.g., tensor veli palatini, levator veli palatini, palatoglossus, palatopharyngeus, and musculus uvulae). Aerodigestive tract muscle sarcopenia or dysfunction disorders may include difficulty with swallowing (dysphagia), eating, drinking, or breathing (e.g., obstructive sleep apnea), voice disorders (e.g., presbyphonia), choking, chronic cough, foodaspiration, regurgitation, geniohyoid muscle atrophy, tongue muscle fatty replacement, and / or pharyngeal muscle volume reduction. Sarcopenia and / or myogenic dysfunction may be caused by aging, lack of exercise, poor nutrition, obesity, congenital defects in the throat or esophagus, injury to the throat or neck caused by trauma or surgery, stroke, brain injury, gastroesophageal reflux disease (GERD), neuromuscular disorders such as myasthenia gravis, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), oculopharyngeal muscular dystrophy, and certain types of peripheral neuropathies; and other diseases such as diabetes, heart disease, rheumatoid arthritis, renal failure, and cancer; as well as certain medications such as corticosteroids, statins, sulfonylureas, androgen receptor inhibitors, glucagon like peptide-1 (GLP-1) receptor agonists, anticholinergic drugs, immune checkpoint inhibitors, and antidiabetic drugs such as metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and insulin.

[0051] “Microenergy acoustic pulse” therapy, as used herein, refers to a treatment comprising application of one or more pulses of acoustic shockwaves having energy in a range from 0.005 mJ / mm.sup2to 0.05 mJ / mm.sup2.

[0052] “Energy flux density” or “EFD” at a point in space is defined as the amount of energy contained in a single acoustic energy pulse passing that point per unit of cross-sectional area orthogonal to the direction of pulse propagation. It is measured in mJ / mm2. All EFD measurements referred to herein are calculated from pressure measurements of acoustic pulses as they pass through water, where the pressure of the pulse at a point in space and time in a water tank is measured with a hydrophone according to standard practice in the industry (International Electrotechnical Commission (IEC)-61846: 1998). The pressure curve as a function of time at a point is converted to the EFD at that point by formulas specified in I EC-61846: 1998.

[0053] An “energy density field" refers to a space through which an acoustic energy pulse travels together with the EFD values at all points within the space.

[0054] The terms “individual”, “subject”, “recipient", and “patient” are used interchangeably herein and refer to any mammalian subject for whom treatment or therapy is desired, particularly humans. "Mammal" for purposes of treatment refers to any animal classified as a mammal, including human and non-human mammals such as non-human primates, including chimpanzees and other apes and monkey species; laboratory animals such as mice, rats, rabbits, hamsters, guinea pigs, and chinchillas; domestic animals such as dogs and cats; and farm animals such as sheep, goats, pigs, horses and cows.

[0055] The term “user” as used herein refers to a person that interacts with a device and / or system disclosed herein for performing one or more steps of the presently disclosed methods. The user maybe the patient receiving treatment for a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder. The user may be a health care practitioner, such as the patient’s physician, a physical therapist, clinician, or nurse.

[0056] The terms "treatment", "treating", "treat" and the like are used herein to generally refer to obtaining a desired pharmacologic and / or physiologic effect. The effect can be prophylactic in terms of completely or partially preventing a disease or symptom(s) thereof and / or may be therapeutic in terms of a partial or complete stabilization or cure for a disease and / or adverse effect attributable to the disease. The term “treatment" encompasses any treatment of a disease in a mammal, particularly a human, and includes: (a) preventing the disease and / or symptom(s) from occurring in a subject who may be predisposed to the disease or symptom but has not yet been diagnosed as having it; (b) inhibiting the disease and / or symptom(s), i.e., arresting their development; or (c) relieving the disease symptom(s), i.e., causing regression of the disease and / or symptom (s). Those in need of treatment include those already inflicted (e.g., those with a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder) as well as those in which prevention is desired those with a genetic predisposition to developing a sarcopenia-related or myogenic dysfunctionbased upper aerodigestive tract disorder, those with increased susceptibility to developing a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder, those experiencing physical trauma (e.g., broken limb) or about to have surgery for an upper aerodigestive tract disorder, etc.).

[0057] A therapeutic treatment is one in which the subject is inflicted prior to administration and a prophylactic treatment is one in which the subject is not inflicted prior to administration. In some embodiments, the subject has an increased likelihood of becoming inflicted or is suspected of being inflicted prior to treatment. In some embodiments, the subject is suspected of having an increased likelihood of becoming inflicted.

[0058] “Treatment" with MAP stimulation, as used herein, refers to application of one or more microenergy acoustic pulses to regenerate and / or strengthen a target tissue of the upper aerodigestive tract (e.g., one or more muscles) being treated to restore normal functioning or improve functioning compared to the condition of the tissue prior to treatment. “The energy field created by the MAP stimulation may fully encompass a target tissue or organ or at least a portion of the target tissue or organ sufficiently to result in a therapeutically effective treatment of the target tissue or organ.

[0059] By "therapeutically effective dose or amount" of MAP stimulation is intended an amount that, when administered as described herein, brings about a positive therapeutic response in treatment of a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder, such asan amount that maintains or increases muscle mass and / or muscle contractility strength, and / or increases proportion of fast-twitch muscle fibers of a muscle of the upper aerodigestive tract, increase tongue pressure and / or jaw-opening force, and / or improves swallowing, breathing, and / or speech vocalization. Additionally, a therapeutically effective dose or amount" of MAP stimulation may reduce numbers of senescent cells in tissue of the upper aerodigestive tract. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, the particular drug or drugs employed, mode of administration, and the like. An appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation, based upon the information provided herein.

[0060] The term “responsive” as used herein means that the treatment is having the desired effect in treatment of a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder. When the individual does not improve in response to the treatment, it may be desirable to seek a different therapy or treatment regime for the individual.

[0061] The terms "connected" or "coupled" are used in an operational sense and are not necessarily limited to a direct connection or coupling. For example, two devices or components may be coupled directly, or via one or more intermediary media or devices. As another example, devices may be coupled in such a way that information or data can be passed between them, while not sharing any physical connection with one another. In some cases, two devices or components may be connected by a wire or wirelessly to each other.Methods

[0062] Methods are provided for administering microenergy acoustic pulse (MAP) stimulation to a subject who has a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder. MAP stimulation of muscles of the upper aerodigestive tract increases muscle mass and contractility strength, increases the proportion of fast-twitch muscle fibers, reduces numbers of senescent cells, and activates muscle stem cells to regenerate muscle tissue. Without being bound by theory, the improvement in muscle function in response to MAP stimulation may be due, in part, to the biological effects of MAP on the Wnt / Frizzled signaling pathway, which lead to conversion of quiescent muscle stem cells (PAX7+MYOD_) to proliferating progenitor cells (PAX7+MYOD+), cell differentiation (PAX7+MYOG+), and muscle regeneration. MAP stimulation also inhibits NOTCH signaling through AGTR1, activates the MAPK and FAK / ERK pathway and the PERK / ATF4 endoplasmic reticulum (ER) stress pathway to enhance muscle stem cell expansion, differentiation, and muscle regeneration.

[0063] The subject methods can be used to regenerate and strengthen upper aerodigestive tract muscles to treat sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorders that cause difficulty with swallowing (dysphagia), eating, drinking, breathing (e.g., obstructive sleep apnea), or speaking (e.g., presbyphonia, vocal fatigue, reduced vocal projection or intensity, tremulous or unstable vocal output, and / or hoarseness), choking, chronic cough, food aspiration, regurgitation, geniohyoid muscle atrophy, tongue muscle fatty replacement, and / or pharyngeal muscle volume reduction. The subject methods can be used to treat sarcopenia and / or myogenic dysfunction caused by aging, lack of exercise, poor nutrition, obesity, congenital defects in the throat or esophagus, injury to the throat or neck caused by trauma or surgery, stroke, brain injury, gastroesophageal reflux disease (GERD), neuromuscular disorders such as myasthenia gravis, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), oculopharyngeal muscular dystrophy, and certain types of peripheral neuropathies; and other diseases such as diabetes, heart disease, rheumatoid arthritis, renal failure, and cancer; as well as certain medications such as corticosteroids, statins, sulfonylureas, androgen receptor inhibitors, glucagon like peptide-1 (GLP-1) receptor agonists, anticholinergic drugs, immune checkpoint inhibitors, and antidiabetic drugs such as metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, dipeptidyl peptidase- 4 (DPP-4) inhibitors, and insulin.

[0064] MAP stimulation is delivered with a shockwave probe. In some embodiments, the shockwave probe is a radial shockwave probe or a focused shockwave probe. A radial shockwave probe disperses shockwaves in a wider radius than a focused shockwave probe, which may be desired to treat a larger area of tissue. A focused shockwave probe concentrates the shockwaves at a specific focus point, which allows for deeper penetration and more precise targeting of tissue.

[0065] The MAP stimulation may be applied using a single shockwave probe or multiple shockwave probes. Using multiple shockwave probes allows a larger area to be treated with shockwaves at a time. In some embodiments, MAP stimulation is delivered to a targeted area using multiple shockwave probes simultaneously or in rapid succession. The use of multiple shockwave probes allows MAP stimulation to be delivered at different angles, to different target regions, at different tissue depths. In some embodiments, one or more shockwave probes are positioned along the neck of a subject to deliver MAP stimulation to one or more target muscles of the upper aerodigestive tract in a manner effective for treating a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder.

[0066] In some embodiments, the number of shockwave probes used to deliver MAP stimulation to one or more muscles of the upper aerodigestive tract is 2 or more, 3 or more, 4 or more, 5 or more, 6 or more, 7 or more, 8 or more, 9 or more, or 10 or more. In some embodiments, the number ofshockwave probes used to deliver MAP stimulation to muscles of the upper aerodigestive tract is in a range of 1 to 20, 1 to 10, or 1 to 5, including any number of shockwave probes in these ranges such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 shockwave probes.

[0067] In some embodiments, the MAP stimulation is applied to more than one site along the upper aerodigestive tract. The site to which the MAP stimulation is applied may be alternated or otherwise spatially or temporally patterned. MAP stimulation may be applied to the sites simultaneously or sequentially. In certain embodiments, the region of the upper aerodigestive tract to which MAP stimulation is applied is the tongue, oral cavity, throat, voice box, esophagus, soft palate, or other region of the upper aerodigestive tract suitable for stimulation. The site chosen for stimulation may differ for different subjects and will depend on the particular sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder a subject has and which muscle (or group of muscles) of the upper aerodigestive tract is in need of treatment. In some embodiments, the target area of the upper aerodigestive tract to be treated with MAP stimulation is divided into a plurality of smaller treatment zones, each of which is treated with MAP stimulation. In some cases, MAP stimulation may be tested at various locations on a trial basis to identify the optimal location for positioning a shockwave probe for delivery of MAP stimulation to maximize relief of symptoms of a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder.

[0068] The subject methods can be used to treat sarcopenia or myogenic dysfunction in various muscles of the upper aerodigestive tract such as, but not limited to, muscles of the tongue (e.g., genioglossus, hyoglossus, styloglossus, palatoglossus, superior longitudinal, inferior longitudinal, transverse, and vertical lingual muscles), oral cavity (e.g., bilateral mylohyoid muscles, buccinator muscle, geniohyoid muscles), throat (e.g., pharyngeal muscles such as the constrictor muscles, including the superior pharyngeal constrictor, middle pharyngeal constrictor, and inferior pharyngeal constrictor muscles; and the elevator muscles, including the palatopharyngeus, salpingopharyngeus, and stylopharyngeus muscles), voice box (e.g., laryngeal muscles such as the thyroarytenoid muscle, vocalis muscle, lateral cricoarytenoid muscle, posterior cricoarytenoid muscle, interarytenoid muscle, suprahyoid muscles, including digastric, stylohyoid, mylohyoid, and geniohyoid muscles; infrahyoid muscles, including sternohyoid, sternothyroid, thyrohyoid, omohyoid muscles), esophagus (e.g., esophageal striated skeletal muscles such as in the upper third of the esophagus, smooth muscles such as in the middle and lower thirds of the esophagus, the upper esophageal sphincter, and the lower esophageal sphincter), and soft palate (e.g., tensor veli palatini, levator veli palatini, palatoglossus, palatopharyngeus, and musculus uvulae).

[0069] For example, MAP stimulation can be administered to genioglossus and related laryngeal muscles to selectively strengthen the tongue and related muscles to propel the tongue forward fortreatment of obstructive sleep apnea. In another example, MAP stimulation can be administered to pharyngeal and related muscles to strengthen pharyngeal and related muscles to improve swallowing function for treatment of dysphagia. In yet another example, MAP stimulation can be administered to laryngeal muscles to strengthen laryngeal and related muscles to improve voicing function for treatment of dysphonia.

[0070] In certain embodiments, the target region of the upper aerodigestive tract is optimized to maximize clinical responses to MAP stimulation to treat a symptom of a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder. In embodiments in which a voice disorder (e.g., presbyphonia) is treated, the target region comprises at least a portion of the voice box, including one or more laryngeal muscles selected from the medial thyroarytenoid muscle (also known as the vocalis muscle), lateral cricoarytenoid muscle, posterior cricoarytenoid muscle, interarytenoid muscle, and / or one or more suprahyoid muscles selected from the digastric, stylohyoid, mylohyoid, and geniohyoid muscles; and / or one or more infrahyoid muscles selected from the sternohyoid, sternothyroid, thyrohyoid, and omohyoid muscles. In embodiments in which a swallowing disorder is treated, the target region comprises at least a portion of the tongue including one or more tongue muscles selected from the genioglossus, hyoglossus, styloglossus, palatoglossus, superior longitudinal, inferior longitudinal, transverse, and vertical lingual muscles; and / or at least a portion of the oral cavity including one or more oral cavity muscles selected from the bilateral mylohyoid muscles, buccinator muscle, and geniohyoid muscles; and / or at least a portion of the throat including one or more throat muscles selected from the pharyngeal muscles such as one or more constrictor muscles selected from the superior pharyngeal constrictor, middle pharyngeal constrictor, and inferior pharyngeal constrictor muscles; and / or one or more elevator muscles selected from the palatopharyngeus, salpingopharyngeus, and stylopharyngeus muscles; and / or at least a portion of the esophagus including one or more esophagus muscles selected from the esophageal striated skeletal muscles such as in the upper third of the esophagus, smooth muscles such as in the middle and lower thirds of the esophagus, the upper esophageal sphincter, and the lower esophageal sphincter.

[0071] In some embodiments, the MAP stimulation is applied to a target region of the upper aerodigestive tract in acoustic pulses at a frequency (i.e., number of shockwaves delivered per second) in a range of 1 Hz to 20 Hz, 1 Hz to 12 Hz, 1 Hz to 5 Hz, or 1 Hz to 3 Hz, including any frequency within these ranges, such as 1 Hz, 2 Hz, 3 Hz, 4 Hz, 5 Hz, 6 Hz, 7 Hz, 8 Hz, 9 Hz, 10 Hz, 11 Hz, 12 Hz, 13 Hz, 14 Hz, 15 Hz, 16 Hz, 17 Hz, 18 Hz, 19 Hz, or 20 Hz. In some embodiments, non-integer pulse frequencies are used (e.g. 3.2 Hz, 3.5 Hz, etc.).

[0072] In some embodiments, the total number of acoustic pulses applied to a target region of the upper aerodigestive tract during a treatment session is in a range of 100 pulses to 2000 pulses, 200 pulses to 1000 pulses, 300 pulses to 700 pulses, or 400 pulses to 600 pulses, including any number of pulses within these ranges, such as 100 pulses, 150 pulses, 200 pulses, 250 pulses, 300 pulses, 350 pulses, 400 pulses, 450 pulses, 500 pulses, 550 pulses, 600 pulses, 650 pulses, 700 pulses, 750 pulses, 800 pulses, 850 pulses, 900 pulses, 950 pulses, 1000 pulses, 1100 pulses, 1200 pulses, 1300 pulses, 1400 pulses, 1500 pulses, 1600 pulses, 1700 pulses, 1800 pulses, 1900 pulses, or 2000 pulses. In some embodiments, the target area of the upper aerodigestive tract to be treated with MAP stimulation is divided into a plurality of smaller treatment zones, wherein each treatment zone is provided with 100 pulses to 2000 pulses, 200 pulses to 1000 pulses, 300 pulses to 700 pulses, or 400 pulses to 600 pulses in a treatment session.

[0073] In certain embodiments, MAP stimulation is applied to a target region of the upper aerodigestive tract with an energy flux density in a range of 0.005 mJ / mm2to 0.05 mJ / mm2, 0.02 mJ / mm2to 0.04 mJ / mm2, or 0.033 mJ / mm2to 0.05 mJ / mm2, including any energy flux density within these ranges, such as 0.005 mJ / mm2, 0.006 mJ / mm2, 0.007 mJ / mm2, 0.008 mJ / mm2, 0.009 mJ / mm2, 0.01 mJ / mm2, 0.015 mJ / mm2, 0.02 mJ / mm2, 0.021 mJ / mm2, 0.022 mJ / mm2, 0.023 mJ / mm2, 0.024 mJ / mm2, 0.025 mJ / mm2, 0.026 mJ / mm2, 0.027 mJ / mm2, 0.028 mJ / mm2, 0.029 mJ / mm2, 0.03 mJ / mm2, 0.031 mJ / mm2, 0.032 mJ / mm2, 0.033 mJ / mm2, 0.034 mJ / mm2, 0.035 mJ / mm2, 0.036 mJ / mm2, 0.037 mJ / mm2, 0.038 mJ / mm2, 0.039 mJ / mm2, 0.04 mJ / mm2, 0.041 mJ / mm2, 0.042 mJ / mm2, 0.043 mJ / mm2, 0.044 mJ / mm2, 0.045 mJ / mm2, 0.046 mJ / mm2, 0.047 mJ / mm2, 0.048 mJ / mm2, 0.049 mJ / mm2, or 0.05 mJ / mm2.

[0074] In certain embodiments, MAP stimulation is applied to a target region of the upper aerodigestive tract with a stimulation duration in a range of 0.1 ms to 20 ms, 0.5 ms to 15 ms, 10 ms to 15 ms, or 5 ms to 10 ms, or any stimulation duration within these ranges such as 0.1 ms, 0.2 ms, 0.3 ms, 0.4 ms, 0.5 ms, 0.6 ms, 0.7 ms, 0.8 ms, 0.9 ms, 1.0 ms, 1.5 ms, 2.0 ms, 2.5 ms, 3.0 ms, 3.5 ms, 4.0 ms, 4.5 ms, 5 ms, 5.5 ms, 6 ms, 6.5 ms, 7 ms, 7.5 ms, 8 ms, 8.5 ms, 9 ms, 9.5 ms, 10 ms, 10.5 ms, 11 ms, 11.5 ms, 12 ms, 12.5 ms, 13 ms, 13.5 ms, 14 ms, 14.5 ms, 15 ms, 15.5 ms, 16 ms, 16.5 ms, 17 ms, 17.5 ms, 18 ms, 18.5 ms, 19 ms, 19.5 ms, or 20 ms.

[0075] In certain embodiments, MAP stimulation is applied to a target region of the upper aerodigestive tract with an acoustic peak pressure in a range from 1 MPa to to 25 MPa, 5 MPa to 10 MPa, or 10 MPa to 20 MPa, including any acoustic peak pressure within these ranges such as 1.0 MPa, 2.0 MPa, 3.0 MPa, 4.0 MPa, 5.0 MPa, 6.0 MPa, 7.0 MPa, 8.0 MPa, 9.0 MPa, 10 MPa, 11 MPa, 12 MPa, 13 MPa, 14 MPa, 15 MPa, 16 MPa, 17 MPa, 18 MPa, 19 MPa, 21 MPa, 22 MPa, 23 MPa, 24 MPa, 25 MPa, or 25 MPa.

[0076] In certain embodiments, the MAP stimulation is applied for a stimulation period in a range of 1 minute to 1 hour, 10 minutes to 30 minutes, 15 minutes to 20 minutes, or 5 minutes to 10 minutes, or any stimulation period in these ranges such as 1 minutes, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 11 minutes, 12 minutes, 13 minutes, 14 minutes, 15 minutes, 16 minutes, 17 minutes, 18 minutes, 19 minutes, 20 minutes, 21 minutes, 22 minutes, 23 minutes, 24 minutes, 25 minutes, 26 minutes, 27 minutes, 28 minutes, 29 minutes, 30 minutes, 31 minutes, 32 minutes, 33 minutes, 34 minutes, 35 minutes, 36 minutes, 37 minutes, 38 minutes, 39 minutes, 40 minutes, 41 minutes, 42 minutes, 43 minutes, 44 minutes, 45 minutes, 46 minutes, 47 minutes, 48 minutes, 49 minutes, 50 minutes, 51 minutes, 52 minutes, 53 minutes, 54 minutes, 55 minutes, 56 minutes, 57 minutes, 58, minutes 59 minutes, or 60 minutes. In some embodiments, a period of rest (i.e. , no MAP stimulation) is added in between periods of MAP stimulation. In some embodiments, MAP stimulation may be applied for a few weeks or more, a month or more, 2 months or more, 3 months or more, 4 months or more, 5 months or more, 6 months or more, a year or more, 2 years or more, 3 years or more, 5 years or more, or 10 years or more. In some embodiments, MAP stimulation is continued indefinitely as part of a long-term MAP therapy regimen.

[0077] As noted above, the treatment may ameliorate a symptom of a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder. Assessment of effectiveness of the treatment may be performed using any known method for evaluating symptoms. The method selected will depend on the particular sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder undergoing treatment with MAP stimulation.

[0078] In some embodiments, efficacy of the treatment of a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder is evaluated by monitoring the subject to detect improvement or lack of improvement in various symptoms of a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder such as difficulty with swallowing (dysphagia), eating, drinking, or breathing (e.g., obstructive sleep apnea), presbyphonia (e.g., vocal fatigue, reduced vocal projection or intensity, tremulous or unstable vocal output, and hoarseness), choking, chronic cough, food aspiration, or regurgitation. In some embodiments, efficacy of the treatment of a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder is evaluated by measuring mass or contractile strength of a muscle of the upper aerodigestive tract. For treatment of dysphagia, the response to MAP stimulation may be evaluated using a water swallow test, a videofluoroscopic swallowing study (VFSS, also known as a modified barium swallow study), or a fiberoptic endoscopic evaluation of swallowing (FEES). For treatment of presbyphonia, the response to MAP stimulation may be evaluated using a vocal performance assessment including pitch range,intensity range, and voice quality measures; vocal recording and analysis including quantification of the voice signal with respect to pitch, loudness, quality and variability; or videolaryngoscopy, For treatment of a breathing disorder, the response to MAP stimulation may be evaluated using a spirometer, a breath monitor, a pulse oximeter, or an arterial blood gas test. For treatment of obstructive sleep apnea, the response to MAP stimulation may be evaluated using polysomnography (PSG), electromyography (EMG), or pulse oximetry.

[0079] Assessment of effectiveness of treatment may be performed at any suitable time point after commencement of the MAP therapy, for example, during or after MAP therapy. Embodiments of the subject methods include assessing effectiveness of MAP stimulation in treating a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder in a subject within seconds, minutes, hours, days, weeks, or months after the initial treatment regimen has been completed. In some instances, assessment may be performed at multiple time points. In some cases, more than one type of assessment may be performed at the different time points. In some embodiments, a symptom of a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder is assessed prior to and after the application of the MAP stimulation, wherein reduced severity of the symptom indicates successful treatment.

[0080] Upon completion of a treatment regimen, the patient may be assessed for effectiveness of the treatment and the treatment regimen may be repeated, if needed. In certain cases, the treatment regimen may be altered before repeating. For example, one or more of the target region of the upper aerodigestive tract, stimulation duration, number of pulses, pulse length, pulse frequency, energy flux density, and pressure amplitude may be altered before starting a second treatment regimen.

[0081] Application of the method may include a prior step of selecting a patient for treatment based on need as determined by clinical assessment, which may include assessment of severity of symptoms of a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder, physical condition, cognitive assessment, anatomical assessment, behavioral assessment and / or neurophysiological assessment. In certain cases, a subject may be further assessed to determine if MAP stimulation will completely or partially (e.g., at least 50%) relieve symptoms. Such a patient may undergo MAP stimulation on a temporary trial basis to determine if MAP stimulation decreases the severity of symptoms experienced by the patient.System and Computer Implemented Methods

[0082] Systems and computer implemented methods are also provided, which can be used in practicing the subject methods. The system generally includes a MAP stimulator comprising one or more shockwave probes operatively coupled to a shockwave generator via an electrical cable. Theshockwave generator may be placed on a mobile platform for ease of transporting the system from place to place within a hospital or medical clinic. Any suitable shockwave probe or shockwave generator may be included in the system, including any commercially available system suitable for performing MAP stimulation to treat a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder. The system may include focused shockwave probes or radial shockwave probes. Commercially available shockwave generators and probes are available, for example, from SoftWave Tissue Regeneration Technologies (Alpharetta, GA), Pervita Medical (Tsim Sha Tsui, Kowloon, Hong Kong), Chattanooga (Dallas, TX), and CuraMedix (Lincoln, Rl).

[0083] In certain embodiments, the shockwave probe is a custom shockwave probe adapted for positioning at a location to deliver MAP stimulation to a target muscle. For example, the shockwave probe may be adapted for positioning at a location to deliver MAP stimulation to a genioglossus muscle and a laryngeal muscle for treatment of obstructive sleep apnea, a pharyngeal muscle for treatment of dysphagia, or a laryngeal muscle for treatment of dysphonia. In certain embodiments, the shockwave probe is adapted for positioning on the neck of a subject.

[0084] In some embodiments, a system is provided comprising a processor programmed to control delivery of MAP stimulation to treat a subject for a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder. The processor can be programmed to perform a computer implemented method that instructs the MAP stimulator to deliver MAP stimulation with a shockwave probe to an upper aerodigestive tract muscle of the subject using a selected set of stimulation parameters. In some embodiments, the computer implemented method further comprises receiving experimental data for a measured response of the upper aerodigestive tract muscle to administering the MAP stimulation using an initial selected set of stimulation parameters, wherein the measured response is used to calculate an efficacy score for treatment of the sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder with the MAP stimulation using the initial selected set of MAP stimulation parameters; using the efficacy score from administering the MAP stimulation using the initial selected set of stimulation parameters to adjust one or more programmed stimulation parameters according to an algorithm control law; and instructing the MAP stimulator to deliver MAP stimulation with the shockwave probe to the subject using the new set of stimulation parameters.

[0085] In certain embodiments, the computer-implemented method is repeated until optimization of the set of MAP stimulation parameters no longer results in further improvement of the efficacy of the treatment of the sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder with the MAP stimulation. In some embodiments, the stimulation parameters that are optimized comprise at least 2, at least 3, or at least 4 MAP stimulation parameters selected from atarget region of the upper aerodigestive tract, stimulation duration, number of pulses, pulse length, pulse frequency, energy flux density, and pressure amplitude. If multiple probes are used to deliver the MAP stimulation, the computer-implemented method may further comprise optimizing the number of probes, positioning of the probes (e.g., distance and angles from target regions undergoing MAP stimulation), target regions to apply MAP stimulation, types of probes (e.g., focused shockwave probe or radial shockwave probe), radius of acoustic shockwaves dispersed from a probe, and depth of shockwave penetration into tissue.

[0086] In some embodiments, the computer-implemented method uses data from measuring the response to the treatment of a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder such as the measured mass or contractile strength of a muscle of the upper aerodigestive tract after treatment with MAP stimulation. In some embodiments in which dysphagia is treated with MAP stimulation, the response to MAP stimulation is measured using a water swallow test, a videofluoroscopic swallowing study (VFSS, also known as a modified barium swallow study), or a fiberoptic endoscopic evaluation of swallowing (FEES). In some embodiments in which presbyphonia is treated with MAP stimulation, the response to MAP stimulation is measured using a vocal performance assessment including pitch range, intensity range, and voice quality measures; vocal recording and analysis including quantification of the voice signal with respect to pitch, loudness, quality and variability; or videolaryngoscopy. In some embodiments in which a breathing disorder is treated with MAP stimulation, the response to MAP stimulation is measured using a spirometer, a breath monitor, a pulse oximeter, or an arterial blood gas test. In some embodiments in which obstructive sleep apnea is treated with MAP stimulation, the response to MAP stimulation is measured using polysomnography (PSG), electromyography (EMG), or pulse oximetry.

[0087] In certain embodiments, the computer implemented method further comprises displaying a user interface configured to receive input from a clinician regarding information about a prescribed MAP therapy regimen to be performed on the subject; and displaying the prescribed MAP therapy regimen after the information is entered by the clinician. In some embodiments, the clinician can edit the information to change the prescribed MAP therapy regimen. In some embodiments, the clinician can adjust a MAP stimulation parameter such as, but not limited to, the target region of the upper aerodigestive tract, stimulation duration, number of pulses, pulse length, pulse frequency, energy flux density, pressure amplitude, or any combination thereof.

[0088] In certain embodiments, the computer implemented method further comprises displaying the experimental data from measuring the response of the upper aerodigestive tract muscle to administering the MAP stimulation.

[0089] In certain embodiments, the display further displays a user interface to allow modification of the MAP therapy by the user, wherein the user can change a stimulation pulse pattern or spatial geometry of the MAP stimulation

[0090] In certain embodiments, the computer implemented method further comprises: displaying a user interface configured to receive input from the subject to allow selection of a video, wherein the video demonstrates how to perform MAP therapy on a selected upper aerodigestive tract muscle; and playing the video on a display viewable by the subject.

[0091] In certain embodiments, the computer implemented method further comprises displaying a user interface presenting a calendar configured to receive input from the subject or a clinician regarding when MAP therapy is scheduled for the subject. In some embodiments, the calendar further tracks when the MAP therapy on the subject is completed.

[0092] In certain embodiments, the computer implemented method further comprises displaying a user interface presenting a questionnaire configured to receive input from the subject regarding selfreported results of the MAP therapy. In some embodiments, the questionnaire comprises patient- reported outcome measures (PROMs), or questions about symptoms such as, but not limited to, difficulties with swallowing (dysphagia), eating, drinking, or breathing (e.g., obstructive sleep apnea), presbyphonia (e.g., vocal fatigue, reduced vocal projection or intensity, tremulous or unstable vocal output, and hoarseness), choking, chronic cough, food aspiration, and regurgitation, and / or other medical concerns.

[0093] In certain embodiments, the computer implemented method further comprises storing the data that is acquired for the subject in a database.

[0094] The methods can be implemented in digital electronic circuitry, or in computer software, firmware, or hardware. The disclosed and other embodiments can be implemented as one or more computer program products, i.e., one or more modules of computer program instructions encoded on a computer readable medium for execution by, or to control the operation of, a data processing apparatus. The computer readable medium can be a machine-readable storage device, a machine- readable storage substrate, a memory device, a composition of matter effecting a machine-readable propagated signal, or any combination thereof.

[0095] A computer program (also known as a program, software, software application, script, or code) can be written in any form of programming language, including compiled or interpreted languages, and it can be deployed in any form, including as a stand-alone program or as a module, component, subroutine, or other unit suitable for use in a computing environment. A computer program does not necessarily correspond to a file in a file system. A program can be stored in a portion of a file that holds other programs or data (e.g., one or more scripts stored in a markuplanguage document), in a single file dedicated to the program in question, or in multiple coordinated files (e.g., files that store one or more modules, sub programs, or portions of code). A computer program can be deployed to be executed on one computer or on multiple computers that are located at one site or distributed across multiple sites and interconnected by a communication network.

[0096] In a further aspect, the system for performing the computer implemented method, as described, may include a processor, a storage component (i.e. , memory), a display component, and other components typically present in general purpose computers. In some embodiments, the processor is provided by a computer or handheld device (e.g., a cell phone or tablet). The storage component stores information accessible by the processor, including instructions that may be executed by the processor and data that may be retrieved, manipulated or stored by the processor.

[0097] The storage component includes instructions. For example, the storage component includes instructions stored therein for instructing a MAP stimulator to deliver MAP stimulation with a shockwave probe to an upper aerodigestive tract muscle of the subject to treat a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder according to the methods described herein. The computer processor is coupled to the storage component and configured to execute the instructions stored in the storage component in order to receive experimental data from measuring a response of the upper aerodigestive tract muscle to administering the MAP stimulation and analyze the data according to a computer implemented method described herein.

[0098] The processor and / or memory may be operably connected to a display device, for example, via a wired, such as a Universal Serial Bus (USB) connection, or wireless connection, such as a Bluetooth connection. Any convenient display device, such as a liquid crystal display (LCD), lightemitting diode (LED) display, plasma (PDP) display, quantum dot (QLED) display or cathode ray tube display device may be used.

[0099] The storage component may be of any type capable of storing information accessible by the processor, such as a hard-drive, memory card, ROM, RAM, DVD, CD-ROM, USB Flash drive, write- capable, and read-only memories. The processor may be a general purpose processor, a graphics processor unit, a digital signal processor (DSP), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA) or other programmable logic device, discrete gate or transistor logic, discrete hardware components, or any combination thereof designed to perform the functions described herein. A general purpose processor can be a microprocessor, but in the alternative, the processor can be a controller, microcontroller, or state machine, combinations of the same, or the like. A processor can also be implemented as a combination of computing devices, e.g., a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration. Although describedherein primarily with respect to digital technology, a processor can also include primarily analog components. A computing environment can include any type of computer system, including, but not limited to, a computer system based on a microprocessor, a graphics processor unit, a mainframe computer, a digital signal processor, a portable computing device, a personal organizer, a device controller, and a computational engine within an appliance, to name a few.

[0100] The steps of a method, process, or algorithm described in connection with the embodiments disclosed herein can be embodied directly in hardware, in a software module executed by a processor, or in a combination of the two. A software module, engine, and associated databases can reside in memory resources such as in RAM memory, FRAM memory, flash memory, ROM memory, EPROM memory, EEPROM memory, registers, hard disk, a removable disk, a CD-ROM, or any other form of non-transitory computer-readable storage medium, media, or physical computer storage known in the art. An exemplary storage medium can be coupled to the processor such that the processor can read information from, and write information to, the storage medium. In the alternative, the storage medium can be integral to the processor. The processor and the storage medium can reside in an ASIC. The ASIC can reside in a user terminal. In the alternative, the processor and the storage medium can reside as discrete components in a user terminal.

[0101] The instructions may be any set of instructions to be executed directly (such as machine code) or indirectly (such as scripts) by the processor. In that regard, the terms "instructions," "steps" and "programs" may be used interchangeably herein. The instructions may be stored in object code form for direct processing by the processor, or in any other computer language including scripts or collections of independent source code modules that are interpreted on demand or compiled in advance.

[0102] Data may be retrieved, stored or modified by the processor in accordance with the instructions. For instance, although the system is not limited by any particular data structure, the data may be stored in computer registers, in a relational database as a table having a plurality of different fields and records, XML documents, or flat files. The data may also be formatted in any computer-readable format such as, but not limited to, binary values, ASCII or Unicode. Moreover, the data may comprise any information sufficient to identify the relevant information, such as numbers, descriptive text, proprietary codes, pointers, references to data stored in other memories (including other network locations) or information which is used by a function to calculate the relevant data.

[0103] In certain embodiments, the processor and storage component may comprise multiple processors and storage components that may or may not be stored within the same physical housing. For example, some of the instructions and data may be stored on removable CD-ROM andothers within a read-only computer chip. Some or all of the instructions and data may be stored in a location physically remote from, yet still accessible by, the processor. Similarly, the processor may comprise a collection of processors which may or may not operate in parallel.

[0104] In some embodiments, the method can be performed using a cloud computing system. In these embodiments, the programming can be exported to a cloud computer, which runs the program, and returns an output to the user.Kits

[0105] Any of the systems or devices for performing MAP therapy or the software designed to be used with MAP therapy for treatment of a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder, as described herein, may be provided in a kit. The kit may also include packaging that includes a compartment, e.g., a sterile compartment, for holding the device. The packaging may be any suitable packaging for holding the device. Examples of packaging and methods of packaging are described in, e.g., U.S. Pat. Nos. 3,755,042, 4,482,053, 4,750,619; U.S. App. Pub. Nos. 20050268573, 20100133133, each of which are incorporated herein by reference.

[0106] In addition to the above components, the subject kits may further include (in certain embodiments) instructions for using a MAP stimulator for treating a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder. These instructions may be present in the subject kits in a variety of forms, one or more of which may be present in the kit. One form in which these instructions may be present is as printed information on a suitable medium or substrate, e.g., a piece or pieces of paper on which the information is printed, in the packaging of the kit, in a package insert, and the like. Yet another form of these instructions is a computer readable medium, e.g., diskette, compact disk (CD), flash drive, and the like, on which the information has been recorded. Yet another form of these instructions that may be present is a website address which may be used via the internet to access the information at a removed site.Utility

[0107] The methods and systems of the present disclosure find use in the treatment of sarcopenia- related or myogenic dysfunction-based upper aerodigestive tract disorders with MAP stimulation. The subject methods can be used to treat sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorders including any condition or disease associated with loss of muscle mass, contractility strength, and / or function of one or more muscles of the upper aerodigestive tract resulting in difficulty with swallowing (dysphagia), eating, drinking, or breathing (e.g., obstructive sleep apnea), impaired voicing function (e.g., presbyphonia), choking, chronic cough, foodaspiration, regurgitation, geniohyoid muscle atrophy, tongue muscle fatty replacement, and / or pharyngeal muscle volume reduction. The sarcopenia and / or presbyphonia myogenic dysfunction may be caused by aging, lack of exercise, poor nutrition, obesity, congenital defects in the throat or esophagus, injury to the throat or neck caused by trauma or surgery, stroke, brain injury, gastroesophageal reflux disease (GERD), neuromuscular disorders such as myasthenia gravis, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), oculopharyngeal muscular dystrophy, and certain types of peripheral neuropathies; and other diseases such as diabetes, heart disease, rheumatoid arthritis, renal failure, and cancer; as well as certain medications such as corticosteroids, statins, sulfonylureas, androgen receptor inhibitors, glucagon like peptide-1 (GLP-1) receptor agonists, anticholinergic drugs, immune checkpoint inhibitors, and antidiabetic drugs such as metformin, sodium-glucose cotransporter 2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, and insulin.Examples of Non-Limiting Aspects of the Disclosure

[0108] Aspects, including embodiments, of the present subject matter described above may be beneficial alone or in combination, with one or more other aspects or embodiments. Without limiting the foregoing description, certain non-limiting aspects of the disclosure numbered 1-67 are provided below. As will be apparent to those of skill in the art upon reading this disclosure, each of the individually numbered aspects may be used or combined with any of the preceding or following individually numbered aspects. This is intended to provide support for all such combinations of aspects and is not limited to combinations of aspects explicitly provided below.1. A method of treating a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder in a subject, the method comprising administering microenergy acoustic pulse (MAP) stimulation to an upper aerodigestive tract muscle of the subject.2. The method of aspect 1, wherein the sarcopenia-related or myogenic dysfunctionbased upper aerodigestive tract disorder is dysphagia, presbyphonia, a breathing disorder, aspiration pneumonia, or obstructive sleep apnea.3. The method of any one of aspects 1-3, wherein the sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder involves geniohyoid muscle atrophy, tongue muscle fatty replacement, pharyngeal muscle volume reduction, vocalis muscle atrophy, or genioglossus muscle atrophy.4. The method of any one of aspects 1-3, wherein the upper aerodigestive tract muscle is a tongue muscle, an oral cavity muscle, a pharyngeal muscle, or a laryngeal muscle.5. The method of aspect 4, wherein the tongue muscle is a genioglossus muscle, a hyoglossus muscle, a styloglossus muscle, a palatoglossus muscle, a superior longitudinal lingual muscle, an inferior longitudinal lingual muscle, a transverse lingual muscle, or a vertical lingual muscle.6. The method of aspect 5, wherein said administering the MAP stimulation comprises administering the MAP stimulation to the genioglossus muscle and the laryngeal muscle for treatment of obstructive sleep apnea.7. The method of aspect 4, wherein said administering the MAP stimulation comprises administering the MAP stimulation to the pharyngeal muscle for treatment of dysphagia.8. The method of aspect 4, wherein said administering the MAP stimulation comprises administering the MAP stimulation to the laryngeal muscle for treatment of dysphonia.9. The method of aspect 4, wherein the laryngeal muscle is a thyroarytenoid muscle, a vocalis muscle, a lateral cricoarytenoid muscle, a posterior cricoarytenoid muscle, an interarytenoid muscle, a suprahyoid muscle, or an infrahyoid muscle.10. The method of aspect 9, wherein the suprahyoid muscle is a digastric muscle, a stylohyoid muscle, a mylohyoid muscle, or a geniohyoid muscle.11. The method of aspect 9, wherein the infrahyoid muscle is a sternohyoid muscle, a sternothyroid muscle, a thyrohyoid muscle, or omohyoid muscle.12. The method of aspect 4, wherein the pharyngeal muscle is a superior pharyngeal constrictor muscle, a middle pharyngeal constrictor muscle, an inferior pharyngeal constrictor muscle, a palatopharyngeus muscle, a salpingopharyngeus muscle, or a stylopharyngeus muscle.13. The method of aspect 4, wherein the oral cavity muscle is a bilateral mylohyoid muscle, a buccinator muscle, or a geniohyoid muscle.14. The method of any one of aspects 1-13, wherein said administering the MAP stimulation increases muscle contractility strength, increases muscle mass, or increases proportion of fast-twitch muscle fibers of the upper aerodigestive tract muscle compared to in absence of said administering the MAP stimulation.15. The method of any one of aspects 1-14, wherein said administering the MAP stimulation decreases numbers of senescent cells in the upper aerodigestive tract muscle compared to in absence of said administering the MAP stimulation.16. The method of any one of aspects 1-15, wherein said administering the MAP stimulation increases tongue pressure or jaw-opening force compared to in absence of said administering the MAP stimulation.17. The method of any one of aspects 1-16, wherein the subject is elderly, bedridden, in intensive care, or has a broken limb.18. The method of any one of aspects 1-17, wherein said administering the MAP stimulation comprises using a shockwave probe to deliver the MAP stimulation to the muscle of the upper aerodigestive tract.19. The method of aspect 18, wherein the shockwave probe is a focused shockwave probe or a radial shockwave probe.20. The method of aspect 18 or 19, further comprising positioning the shockwave probe at a location on the neck of the subject to deliver the MAP stimulation to the muscle of the upper aerodigestive tract.21. The method of any one of aspects 1-20, wherein said administering the MAP stimulation comprises administering the MAP stimulation with an energy flux density in a range from 0.033 mJ / mm2to 0.05 mJ / mm2.22. The method of any one of aspects 1-21 wherein multiple cycles of MAP stimulation are administered to the subject.23. The method of aspect 22 wherein the MAP stimulation is administered daily or intermittently.24. The method of any one of aspect 23 wherein the MAP stimulation is administered two or three times a week.25. The method of any one of aspects 1-24, further comprising assessing effectiveness of the MAP stimulation in treating the sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder.26. The method of aspect 25, wherein said assessing effectiveness comprises measuring mass or contractile strength of the muscle of the upper aerodigestive tract.27. The method of aspect 25 or 26, wherein said assessing effectiveness comprises performing a water swallow test, a videofluoroscopic swallowing study, a fiberoptic endoscopic evaluation of swallowing, a vocal performance assessment, an analysis of a vocal recording of the subject, a videolaryngoscopy, an analysis of breathing with a spirometer or a breath monitor, pulse oximetry, an arterial blood gas test, polysomnography (PSG), or electromyography (EMG).28. A method of maintaining or increasing muscle mass or contractility strength of an upper aerodigestive tract muscle or regenerating the upper aerodigestive tract muscle, the method comprising administering microenergy acoustic pulse (MAP) stimulation to the upper aerodigestive tract muscle.29. The method of aspect 28, wherein the upper aerodigestive tract muscle is a tongue muscle, an oral cavity muscle, a pharyngeal muscle, or a laryngeal muscle.30. The method of aspect 29, wherein the tongue muscle is a genioglossus muscle, a hyoglossus muscle, a styloglossus muscle, a palatoglossus muscle, a superior longitudinal lingual muscle, an inferior longitudinal lingual muscle, a transverse lingual muscle, or a vertical lingual muscle.31. The method of aspect 29, wherein the laryngeal muscle is a thyroarytenoid muscle, a vocalis muscle, a lateral cricoarytenoid muscle, a posterior cricoarytenoid muscle, an interarytenoid muscle, a suprahyoid muscle, or an infrahyoid muscle.32. The method of aspect 31, wherein the suprahyoid muscle is a digastric muscle, a stylohyoid muscle, a mylohyoid muscle, or a geniohyoid muscle.33. The method of aspect 31, wherein the infrahyoid muscle is a sternohyoid muscle, a sternothyroid muscle, a thyrohyoid muscle, or omohyoid muscle.34. The method of aspect 29, wherein the pharyngeal muscle is a superior pharyngeal constrictor muscle, a middle pharyngeal constrictor muscle, an inferior pharyngeal constrictor muscle, a palatopharyngeus muscle, a salpingopharyngeus muscle, or a stylopharyngeus muscle.35. The method of aspect 29, wherein the oral cavity muscle is a bilateral mylohyoid muscle, a buccinator muscle, or a geniohyoid muscle.36. The method of any one of aspects 28-35, wherein said administering the MAP comprises using a shockwave probe to deliver the MAP stimulation to the muscle of the upper aerodigestive tract.37. The method of aspect 36, wherein the shockwave probe is a focused shockwave probe or a radial shockwave probe.38. The method of aspect 36 or 37, further comprising positioning the shockwave probe at a location on the neck of the subject to deliver the MAP stimulation to the muscle of the upper aerodigestive tract.39. The method of any one of aspects 28-38, wherein said administering the MAP comprises administering the MAP stimulation with an energy flux density of 0.033 mJ / mm2to 0.05 mJ / mm2.40. The method of any one of aspects 28-39, wherein multiple cycles of MAP stimulation are administered to the subject.41. The method of aspect 40, wherein the MAP stimulation is administered daily or intermittently.42. The method of aspect 41, wherein the MAP stimulation is administered two or three times a week.43. The method of any one of aspects 28-42, further comprising assessing effectiveness of the MAP stimulation in treating the sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder.44. The method of aspect 43, wherein said assessing effectiveness comprises measuring mass or contractile strength of the muscle of the upper aerodigestive tract.45. The method of aspect 43 or 44, wherein assessing effectiveness comprises performing a water swallow test, a videofluoroscopic swallowing study, a fiberoptic endoscopic evaluation of swallowing, a vocal performance assessment, an analysis of a vocal recording of the subject, a videolaryngoscopy, an analysis of breathing with a spirometer or a breath monitor, pulse oximetry, an arterial blood gas test, polysomnography (PSG), or electromyography (EMG).46. A method of activating endogenous stem cells to regenerate muscle tissue in an upper aerodigestive tract muscle of a subject, the method comprising administering microenergy acoustic pulse (MAP) stimulation to the upper aerodigestive tract muscle.47. The method of aspect 46, wherein the upper aerodigestive tract muscle is a tongue muscle, an oral cavity muscle, a pharyngeal muscle, or a laryngeal muscle.48. The method of aspect 47, wherein the tongue muscle is a genioglossus muscle, a hyoglossus muscle, a styloglossus muscle, a palatoglossus muscle, a superior longitudinal lingual muscle, an inferior longitudinal lingual muscle, a transverse lingual muscle, or a vertical lingual muscle.49. The method of aspect 47, wherein the laryngeal muscle is a thyroarytenoid muscle, a vocalis muscle, a lateral cricoarytenoid muscle, a posterior cricoarytenoid muscle, an interarytenoid muscle, a suprahyoid muscle, or an infrahyoid muscle.50. The method of aspect 49, wherein the suprahyoid muscle is a digastric muscle, a stylohyoid muscle, a mylohyoid muscle, or a geniohyoid muscle.51. The method of aspect 49, wherein the infrahyoid muscle is a sternohyoid muscle, a sternothyroid muscle, a thyrohyoid muscle, or omohyoid muscle.52. The method of aspect 47, wherein the pharyngeal muscle is a superior pharyngeal constrictor muscle, a middle pharyngeal constrictor muscle, an inferior pharyngeal constrictor muscle, a palatopharyngeus muscle, a salpingopharyngeus muscle, or a stylopharyngeus muscle.53. The method of aspect 47, wherein the oral cavity muscle is a bilateral mylohyoid muscle, a buccinator muscle, or a geniohyoid muscle.54. A system for performing microenergy acoustic pulse (MAP) therapy, the system comprising:a MAP generator;a shockwave probe operatively coupled to the MAP generator, wherein the shockwave probe is adapted for positioning at a location to deliver MAP stimulation to a muscle of the upper aerodigestive tract of a subject; anda processor programmed to instruct the shockwave probe to deliver the MAP stimulation to the upper aerodigestive tract of the subject using the shockwave probe in a manner effective to treat a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder in the subject.55. The system of aspect 54, wherein the shockwave probe is a focused shockwave probe or a radial shockwave probe.56. The system of aspect 54 or 55, wherein the sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder is dysphagia, presbyphonia, a breathing disorder, aspiration pneumonia, or obstructive sleep apnea.57. The system of aspect 56, wherein the shockwave probe is adapted for positioning at a location to deliver MAP stimulation to a genioglossus muscle and a laryngeal muscle for treatment of the obstructive sleep apnea.58. The system of aspect 56, wherein the shockwave probe is adapted for positioning at a location to deliver MAP stimulation to a pharyngeal muscle for treatment of the dysphagia.59. The system of aspect 56, wherein the shockwave probe is adapted for positioning at a location to deliver MAP stimulation to a laryngeal muscle for treatment of the dysphonia.60. The system of any one of aspects 54-59, wherein the shockwave probe is adapted for positioning on the neck of the subject.61. The system of any one of aspects 54-60, wherein the system further comprises a user interface comprising an input electronically coupled to the processor for instructing the shockwave probe to deliver MAP stimulation to the subject to treat the sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder.62. The system of aspect 61 , wherein the user interface is password protected and is operable by a health care practitioner.63. The system of aspect 62, wherein the user interface is configured to receive input from the health care practitioner for one or more parameters of the MAP stimulation, wherein the one or more parameters are selected from a target region of the upper aerodigestive tract, stimulation duration, number of pulses, pulse length, pulse frequency, energy flux density, and pressure amplitude.64. The system of any one of aspects 54-63, further comprising a storage component for storing data, wherein the storage component is coupled to the processor.65. The system of any one of aspects 54-64, further comprising a display for displaying information about the MAP therapy.66. The system of aspect 65, wherein the display further displays a user interface presenting a questionnaire configured to receive input from the subject regarding self-reported results of treatment with the MAP stimulation.67. The system of aspect 65 or 66, wherein the display further displays a user interface to allow modification of the MAP therapy by a user, wherein the user can change a stimulation pulse pattern or spatial geometry of the MAP stimulation.

[0109] It will be apparent to one of ordinary skill in the art that various changes and modifications can be made without departing from the spirit or scope of the invention.EXPERIMENTAL

[0110] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Centigrade, and pressure is at or near atmospheric.

[0111] All publications and patent applications cited in this specification are herein incorporated by reference as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference.

[0112] The present invention has been described in terms of particular embodiments found or proposed by the present inventor to comprise preferred modes for the practice of the invention. It will be appreciated by those of skill in the art that, in light of the present disclosure, numerous modifications and changes can be made in the particular embodiments exemplified without departing from the intended scope of the invention. For example, due to codon redundancy, changes can be made in the underlying DNA sequence without affecting the protein sequence. Moreover, due to biological functional equivalency considerations, changes can be made in protein structure without affecting the biological action in kind or amount. All such modifications are intended to be included within the scope of the appended claims.Example 1Microenerqy Acoustic Pulse Stimulation Applications

[0113] Microenergy acoustic pulse (MAP) stimulation of resident stem / progenitor cells to regenerate muscle has been demonstrated by this research team and others in preclinical animal models. MAP stimulation effects include: 1) enhanced tissue-resident progenitor cell activation, revascularization, and neural regeneration after injury; 2) improved recovery of striated muscle; 3) activated muscle stem cells both in vitro and in vivo preparations; and 4) augmented myotube formation of myoblast cells. Translation of MAP stimulation for the treatment of stress urinary incontinence has already yielded excellent phase I & II clinical trial outcomes in women between 36 to 70 years old.

[0114] Here, we describe MAP stimulation of the upper aerodigestive tract, another organ system comprised of muscle slings and sphincters, to develop innovative treatments for swallowing, voicing, and breathing disorders. Our goal is to develop minimally invasive and effective regenerative therapies for patients with sarcopenia-related and myogenic dysfunction-based upper aerodigestive tract disorders. Without being bound by theory, MAP stimulation of upper aerodigestive tract muscles activates tissue resident stem / progenitor cells that contribute to regeneration and functional recovery. MAP stimulation combined with myostatin inhibition of upper aerodigestive tract muscles enhances regeneration and functional recovery.Example 2MAP stimulation effects on upper aerodigestive tract striated muscles (tongue, laryngeal, and pharyngeal) in an aged rat model

[0115] MAP stimulation is applied to an experimental cohort of aged animals and compared against the non-stimulated control cohort of matched aged animals. Assessments of MAP stimulation on muscle use our published histological, senescence-associated ^-galactosidase activity, and functional ex vivo methods. Assessments of MAP stimulated muscles focus on: 1) regeneration; 2) senescence, and 3) function (contractility and fatiguability). Among unmet clinical needs that may be addressed by this innovative treatment approach are age-related oropharyngeal dysphagia and aspiration pneumonia, presbyphonia, and obstructive sleep apnea.

[0116] Experimental Design: Forty-eight female and male Sprague-Dawley rats aged at 12 months are used for the study. Rats are randomly divided into two cohorts: (A) Control and (B) MAP-stimulated. Each group consists of 24 rats: 12 for functional study and 12 for histological study. The aged rat control group undergoes a sham stimulation procedure. The application of MAP is performed using a compact electromagnetic unit equipped with an unfocused acoustic pulse source (Lite-Med Inc., Taipei, Taiwan). The shockwave probe is positioned directly on the anterior neck (FIG. 1) of the animal, targeting muscles of the upper aerodigestive tract, including the larynx, pharynx, and tongue. Ultrasound gel (Aquasonic, Parker Laboratories Inc., Fairfield, NJ, USA) is applied to ensure effective skin coupling. The MAP protocol in experimental animals is two stimulation sessions weekly for 4 continuous weeks. A MAP stimulation session consists of 500 total pulses delivered at 3 Hz at an energy flux density of 0.033 mJ / mm2. Following a 10-day washout period, the animals undergo in vitro and in vivo tests as described in Exp. 1A, 1B, 1C, and 1D.

[0117] Exp1A: Histological and molecular biological assays. Upper aerodigestive tract tissues are labeled with antibodies against F-actin (phalloidin), striated muscle myosin heavy chain (MHC), a-smooth muscle actin (SMA) to identify the muscles; LOXL-1, laminin and collagen-IV staining to identify the extracellular matrix fiber distributions; von Willebrand factor (vWF), rat endothelial cell antigen (RECA) to identify the endothelium; vesicular choline transporter (VAChT), tyrosine hydroxylase (TH) and neuronal nitric oxide synthase (nNOS) to identify cholinergic, adrenergic and nNOS- (+) nerves. Alpha-BTX labeling is used to identify neuromuscular junctions (NMJs).63, 64 Satellite cells are identified by dual labeling with antibodies recognizing PAX7, CD34, or integrina765, ee T g localization, numbers, and expression level of these parameters are statistically analyzed.

[0118] H&E staining of tissues is performed as previously reported.02Sections transverse to the long axis of muscles are analyzed using the MyoSight semi-automated technique to extract cross- sectional area and minimum Feret diameter measurements. For senescent cell counts, cryosections of muscle tissue are stained to measure SA-|3-Gal activity. The tissue samples are embedded in Optimal Cutting Temperature (OCT) compound, sectioned at a thickness of 10 pm, and allowed to air-dry. After rehydration in PBS, the staining procedure is performed using the senescence - galactosidase staining kit (CST, #9860). The process involves an initial fixation period of 12 minutes, followed by incubation in the staining solution at 37°C for 12 hours.

[0119] Exp1B: In vitro muscle functional tests. Muscle is harvested from animals and placed in an ex vivo organ bath to measure muscle contractility in accordance with our established protocol.67Using a vertical tissue bath system (Myobath Tissue Bath System II, World Precision Instruments, Sarasota, FL), each 10 mL chamber is filled with Krebs solution (NaCI, 86.87 mN; KCI, 5.16 mM;MgS04, 1.22 mM; NaHCOa, 25.56 mM; CaCfe, 1.33 mM and dextrose, 1.01 mM, pH 7.6). The bath is maintained at 37°C and continuously aerated with 95% O2 and 5% CO2. Through an L-shaped metal wire, the ring-shaped urethral segment is connected to a force-displacement transducer (FORT 25, World Precision Instruments).

[0120] Before the start of muscle contractility measurements, we calibrate the force transducer to ensure comparability of data generated at different channels across different times. We initially apply a 5-gm force load and record the corresponding voltage readout. Force load is subsequently lowered to obtain a calibration curve below 1 gm. Thereafter, the muscle length is adjusted to generate a 1 gm resting tension for 30 min. The muscle contractile activity (MCA) measurement is expressed in Newtons (N) per square centimeter (N / cm2). The recorded muscle force is first converted to gram force based on calibration results and then the MCA is calculated using the following formula: MCA (N / cm2) = (force (gm) x muscle length (cm) x 1.06) / (muscle weight (gm) x 0.00981).68

[0121] Exp1C: Electrical Field Stimulation (EFS) Contractility. To measure the muscle contractile response to electrical stimulation, EFS is applied through a pair of platinum electrodes placed on both sides of each preparation. The electrodes run the length of the preparation and are positioned a sufficient distance (~0.5 cm) apart to ensure the muscle is field stimulated, not direct contact stimulated by an electrode. EFS is applied using an electronic stimulator connected to the electrodes. For EFS with single pulses, square-wave stimuli between 10 mA to 70 mA intensity and 0.2 ms duration are delivered. Between each activated contraction, there is a 3 min pause. For the fatiguing stimulation protocol, multipulse EFS with square-wave stimuli of maximal intensity (70 mA) are delivered at a frequency of 5 Hz for 2 min.

[0122] Exp1D: Caffeine Induced Contractility. Caffeine, as a releaser of calcium from intracellular stores, is sourced from Sigma-Aldrich (St. Louis, MO, USA). Caffeine is initially dissolved in citrate buffer and then dissolved in Krebs’ solution to the desired concentration. At the start of caffeine induced contractility measurements, Krebs’ solution in an organ bath is exchanged by adding caffeine-containing Krebs’ solution to trigger muscle activity until muscle contraction reaches a plateau for 10 minutes. The isometric tension is recorded using a semi-automated data acquisition system (Lab TRAX-4, World Precision Instrument).

[0123] MAP stimulation is expected to enhance muscle regeneration, reduce senescence, and improve muscle function in aged rats. Specifically, MAP-treated animals are anticipated to show increased satellite cell activation, improved myotube formation, and better extracellular matrix organization, evidenced by elevated laminin and collagen-IV expression compared to controls.Regarding senescence, MAP treatment is expected to decrease senescent cell burden, as indicated by lower SA- -Gal activity and reduced expression of senescence-associated markers such as p16AINK4a. Functionally, MAP-treated muscles are anticipated to exhibit improved contractility and reduced fatigability in ex vivo assays, with higher maximum force generation and sustained responses during fatigue protocols. Enhanced neuromuscular junction (NMJ) integrity, demonstrated through a-BTX labeling, is also expected in the MAP-treated group.PRELIMINARY DATA

[0124] Overview. Data captured from a pilot experiment demonstrates project feasibility and provides promising early evidence MAP stimulation enhances upper aerodigestive tract muscle structure and function. The cohort contrast study design (FIG. 1) deploys the MAP stimulation protocol detailed in the Methods section. Findings include muscle regeneration by hypertrophy or hyperplasia, senescence reversal, and contractility strengthening. Twenty female Sprague-Dawley aged rats (9 months old) were purchased from Charles River Laboratories (Wilmington, MA, USA) and randomly assigned to two cohorts, MAP (N=10) and Control (N=10).

[0125] Cross-sectional Area and Minimum Feret Diameter Muscle Measurements. Myofibers of MAP stimulated animals have larger transverse cross-sectional area and larger minimum Feret diameter (FIG. 2), indicating muscle regeneration by hypertrophy or hyperplasia.

[0126] Senescence-Associated p-Galactosidase Activity. The tongue and sternohyoid muscles of MAP-stimulated animals have lower senescent cell counts (FIG. 4). (a) Histology of senescent cells (X-gal +) in tongue (transverse / vertical, superior longitudinal), sternohyoid, and genioglossus muscles (Control vs MAP stimulated), (b) MAP stimulated cohort has fewer senescent cells (X-gal +) in the tongue (*P<0.001) and sternohyoid (*P<0.05) muscles, (c) Both transverse vertical and superior longitudinal muscle types of the tongue in MAP stimulated animals have fewer senescent cells (X-gal +) (*p < 0.05).Example 3Molecular mechanisms of MAP stimulation for regeneration of upper aerodioestive tract muscle stem / progenitor cells in vivo and in vitro

[0127] We isolate the muscle stem cells within upper aerodigestive tract muscles using magnetic- activated cell sorting (MACS) and explore the biological effect of MAP on them, including relatedmyogenesis and cellular signaling pathways. We determine which molecular pathways are activated by interrogating Wnt / Frizzle and IGF cellular signaling pathways, and cell senescence. These experiments provide comprehensive data on the mechanisms by which MAP promotes muscle stem cell differentiation and muscle regeneration.

[0128] Experiment 2A: Muscle Stem Cell Isolation and Characterization. To isolate primary, untouched satellite cells (SCs) from the striated muscles of the upper aerodigestive tract (tongue, laryngeal, and pharyngeal), muscle tissue are dissected from freshly euthanized rats and washed in PBS. For the tongue, a 27-gauge needle is carefully inserted into the subepithelial space through the posterior cut surface of the tongue without perforating the epithelial layer, maintaining the needle parallel to the muscle fibers. An enzymatic cocktail, comprising 0.1% Collagenase A (Roche), 0.2% Dispase II (Wako), and 1% penicillin-streptomycin (Wako) in Dulbecco’s Modified Eagle Medium (DMEM, Wako) — is slowly injected while gradually withdrawing the syringe. This process is repeated at four strategic locations (ventral, dorsal, and lateral regions) of the exposed cut tongue surface to ensure maximal distribution of the digestion buffer. The tongue is then transferred to a 1.5 mL tube and incubated at 37°C for 30 minutes.

[0129] Following incubation, blunt tweezers are used to carefully deglove the intact epithelial layer from the underlying muscle tissue. The separated muscle is washed with PBS and subjected to further enzymatic digestion using 0.2 mg / mL Collagenase II (Wako) and 0.1% Dispase for 1 hour at 37°C. The digested muscle is then be minced, triturated with a pipette, and filtered through a 40 pm filter. Magnetic cell sorting (MACS) is subsequently employed to enrich for SCs. This involves using magnetic beads conjugated to a cocktail of antibodies targeting lineage markers (CD11b, CD31, CD45, and Sca-1; Miltenyi #130-104-268) and LS Columns (Miltenyi). The enriched SCs are resuspended in growth medium consisting of 20% FBS (Nishirei), DMEM-Ham’s F12 (Wako), 2.5 ng / mL hFGF-2 (PeproTech), and 1% penicillin-streptomycin, then plated onto Matrigel-coated (Corning) plastic plates or glass coverslips. Cells are maintained at 37°C in a humidified atmosphere containing 5% CO2.

[0130] Experiment 2B: To explore the effect of MAP on tissue resident stem cells in the muscle of upper aerodigestive tract and the molecular mechanism. Twenty-four female and male Sprague-Dawley rats aged at 12 months are used for the study. Rats are randomly assigned to two cohorts: (A) Controls (N=12) and (B) MAP-stimulated (N=12). MAP stimulation procedure as in FIG. 1. After 7-10 days washout, animals are used for stem cell isolation. Muscle stem cells (satellite cells) are isolated from the striated muscles of the upper aerodigestive tract (tongue,laryngeal, and pharyngeal) harvested from treated and control rats, following established methods.66Once isolated, the cells are incubated with primary antibodies conjugated with Alexa 488-azide, specifically targeting Pax7 (AB-528428, Tokyo Institute of Technology), Integrin a-7 (sc-81807, Santa Cruz Biotechnology, Inc.), and H3P (EMD Millipore Corporation, CA, USA). To serve as a signal control, the cells are also be treated with a Click-iT reaction cocktail conjugated with Alexa594- azide (EdU Click-iT Cat# C10339; Invitrogen) for 30 minutes at room temperature.

[0131] Following incubation, the cells are subjected to fluorescence-activated cell sorting (FACS) analysis using a FACS Vantage SE System (BD Biosciences). The flow cytometric data are processed and analyzed with FlowJo software (Tree Star, Inc., Ashland, OR). The analysis focuses on progenitor cell markers, including Pax7, MyoD, and Notch signaling components, to evaluate progenitor cell activation. Additionally, senescence markers such as p16AINK4a and |3-galactosidase activity are quantified to assess cellular senescence within the isolated populations.

[0132] The muscle stem cells isolated through the aforementioned procedures are utilized to study the mechanisms of muscle regeneration and associated signaling pathways in vitro.

[0133] Evaluation of Myogenic Potential Through Differentiation Assays: To investigate the myogenic potential of muscle stem cells, the isolated cells are divided into two groups: a control group and an experimental group treated with varying doses of MAP. The differentiation potential of these cells are then assessed through the following steps:

[0134] Staining to Evaluate Myotube Formation: Specific antibodies, such as MyHC, are used to stain the cells. This allows observation and documentation of the formation and structure of myotubes.

[0135] Quantitative Analysis of Myotubes: Myotube width, length, and number are quantified to compare differences between the control and experimental groups. These experiments provide both quantitative and qualitative data to determine whether MAP can enhance myotube formation and maturation.REFERENCES

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Claims

What is claimed is:

1. A method of treating a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder in a subject, the method comprising administering microenergy acoustic pulse (MAP) stimulation to an upper aerodigestive tract muscle of the subject.

2. The method of claim 1, wherein the sarcopenia-related or myogenic dysfunctionbased upper aerodigestive tract disorder is dysphagia, presbyphonia, a breathing disorder, aspiration pneumonia, or obstructive sleep apnea.

3. The method of any one of claims 1-3, wherein the sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder involves geniohyoid muscle atrophy, tongue muscle fatty replacement, pharyngeal muscle volume reduction, vocalis muscle atrophy, or genioglossus muscle atrophy.

4. The method of any one of claims 1-3, wherein the upper aerodigestive tract muscle is a tongue muscle, an oral cavity muscle, a pharyngeal muscle, or a laryngeal muscle.

5. The method of claim 4, wherein the tongue muscle is a genioglossus muscle, a hyoglossus muscle, a styloglossus muscle, a palatoglossus muscle, a superior longitudinal lingual muscle, an inferior longitudinal lingual muscle, a transverse lingual muscle, or a vertical lingual muscle.

6. The method of claim 5, wherein said administering the MAP stimulation comprises administering the MAP stimulation to the genioglossus muscle and the laryngeal muscle for treatment of obstructive sleep apnea.

7. The method of claim 4, wherein said administering the MAP stimulation comprises administering the MAP stimulation to the pharyngeal muscle for treatment of dysphagia.

8. The method of claim 4, wherein said administering the MAP stimulation comprises administering the MAP stimulation to the laryngeal muscle for treatment of dysphonia.

9. The method of claim 4, wherein the laryngeal muscle is a thyroarytenoid muscle, a vocalis muscle, a lateral cricoarytenoid muscle, a posterior cricoarytenoid muscle, an interarytenoid muscle, a suprahyoid muscle, or an infrahyoid muscle.

10. The method of claim 9, wherein the suprahyoid muscle is a digastric muscle, a stylohyoid muscle, a mylohyoid muscle, or a geniohyoid muscle.

11. The method of claim 9, wherein the infrahyoid muscle is a sternohyoid muscle, a sternothyroid muscle, a thyrohyoid muscle, or omohyoid muscle.

12. The method of claim 4, wherein the pharyngeal muscle is a superior pharyngeal constrictor muscle, a middle pharyngeal constrictor muscle, an inferior pharyngeal constrictor muscle, a palatopharyngeus muscle, a salpingopharyngeus muscle, or a stylopharyngeus muscle.

13. The method of claim 4, wherein the oral cavity muscle is a bilateral mylohyoid muscle, a buccinator muscle, or a geniohyoid muscle.

14. The method of any one of claims 1-13, wherein said administering the MAP stimulation increases muscle contractility strength, increases muscle mass, or increases proportion of fast-twitch muscle fibers of the upper aerodigestive tract muscle compared to in absence of said administering the MAP stimulation.

15. The method of any one of claims 1-14, wherein said administering the MAP stimulation decreases numbers of senescent cells in the upper aerodigestive tract muscle compared to in absence of said administering the MAP stimulation.

16. The method of any one of claims 1-15, wherein said administering the MAP stimulation increases tongue pressure or jaw-opening force compared to in absence of said administering the MAP stimulation.

17. The method of any one of claims 1-16, wherein the subject is elderly, bedridden, in intensive care, or has a broken limb.

18. The method of any one of claims 1-17, wherein said administering the MAP stimulation comprises using a shockwave probe to deliver the MAP stimulation to the muscle of the upper aerodigestive tract.

19. The method of claim 18, wherein the shockwave probe is a focused shockwave probe or a radial shockwave probe.

20. The method of claim 18 or 19, further comprising positioning the shockwave probe at a location on the neck of the subject to deliver the MAP stimulation to the muscle of the upper aerodigestive tract.

21. The method of any one of claims 1-20, wherein said administering the MAP stimulation comprises administering the MAP stimulation with an energy flux density in a range from 0.033 mJ / mm2to 0.05 mJ / mm2.

22. The method of any one of claims 1-21 wherein multiple cycles of MAP stimulation are administered to the subject.

23. The method of claim 22 wherein the MAP stimulation is administered daily or intermittently.

24. The method of any one of claim 23 wherein the MAP stimulation is administered two or three times a week.

25. The method of any one of claims 1-24, further comprising assessing effectiveness of the MAP stimulation in treating the sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder.

26. The method of claim 25, wherein said assessing effectiveness comprises measuring mass or contractile strength of the muscle of the upper aerodigestive tract.

27. The method of claim 25 or 26, wherein said assessing effectiveness comprises performing a water swallow test, a videofluoroscopic swallowing study, a fiberoptic endoscopic evaluation of swallowing, a vocal performance assessment, an analysis of a vocal recording of thesubject, a videolaryngoscopy, an analysis of breathing with a spirometer or a breath monitor, pulse oximetry, an arterial blood gas test, polysomnography (PSG), or electromyography (EMG).

28. A method of maintaining or increasing muscle mass or contractility strength of an upper aerodigestive tract muscle or regenerating the upper aerodigestive tract muscle, the method comprising administering microenergy acoustic pulse (MAP) stimulation to the upper aerodigestive tract muscle.

29. The method of claim 28, wherein the upper aerodigestive tract muscle is a tongue muscle, an oral cavity muscle, a pharyngeal muscle, or a laryngeal muscle.

30. The method of claim 29, wherein the tongue muscle is a genioglossus muscle, a hyoglossus muscle, a styloglossus muscle, a palatoglossus muscle, a superior longitudinal lingual muscle, an inferior longitudinal lingual muscle, a transverse lingual muscle, or a vertical lingual muscle.

31. The method of claim 29, wherein the laryngeal muscle is a thyroarytenoid muscle, a vocalis muscle, a lateral cricoarytenoid muscle, a posterior cricoarytenoid muscle, an interarytenoid muscle, a suprahyoid muscle, or an infrahyoid muscle.

32. The method of claim 31, wherein the suprahyoid muscle is a digastric muscle, a stylohyoid muscle, a mylohyoid muscle, or a geniohyoid muscle.

33. The method of claim 31, wherein the infrahyoid muscle is a sternohyoid muscle, a sternothyroid muscle, a thyrohyoid muscle, or omohyoid muscle.

34. The method of claim 29, wherein the pharyngeal muscle is a superior pharyngeal constrictor muscle, a middle pharyngeal constrictor muscle, an inferior pharyngeal constrictor muscle, a palatopharyngeus muscle, a salpingopharyngeus muscle, or a stylopharyngeus muscle.

35. The method of claim 29, wherein the oral cavity muscle is a bilateral mylohyoid muscle, a buccinator muscle, or a geniohyoid muscle.

36. The method of any one of claims 28-35, wherein said administering the MAP comprises using a shockwave probe to deliver the MAP stimulation to the muscle of the upper aerodigestive tract.

37. The method of claim 36, wherein the shockwave probe is a focused shockwave probe or a radial shockwave probe.

38. The method of claim 36 or 37, further comprising positioning the shockwave probe at a location on the neck of the subject to deliver the MAP stimulation to the muscle of the upper aerodigestive tract.

39. The method of any one of claims 28-38, wherein said administering the MAP comprises administering the MAP stimulation with an energy flux density of 0.033 mJ / mm2to 0.05 mJ / mm2.

40. The method of any one of claims 28-39, wherein multiple cycles of MAP stimulation are administered to the subject.

41. The method of claim 40, wherein the MAP stimulation is administered daily or intermittently.

42. The method of claim 41 , wherein the MAP stimulation is administered two or three times a week.

43. The method of any one of claims 28-42, further comprising assessing effectiveness of the MAP stimulation in treating the sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder.

44. The method of claim 43, wherein said assessing effectiveness comprises measuring mass or contractile strength of the muscle of the upper aerodigestive tract.

45. The method of claim 43 or 44, wherein assessing effectiveness comprises performing a water swallow test, a videofluoroscopic swallowing study, a fiberoptic endoscopic evaluation of swallowing, a vocal performance assessment, an analysis of a vocal recording of the subject, avideolaryngoscopy, an analysis of breathing with a spirometer or a breath monitor, pulse oximetry, an arterial blood gas test, polysomnography (PSG), or electromyography (EMG).

46. A method of activating endogenous stem cells to regenerate muscle tissue in an upper aerodigestive tract muscle of a subject, the method comprising administering microenergy acoustic pulse (MAP) stimulation to the upper aerodigestive tract muscle.

47. The method of claim 46, wherein the upper aerodigestive tract muscle is a tongue muscle, an oral cavity muscle, a pharyngeal muscle, or a laryngeal muscle.

48. The method of claim 47, wherein the tongue muscle is a genioglossus muscle, a hyoglossus muscle, a styloglossus muscle, a palatoglossus muscle, a superior longitudinal lingual muscle, an inferior longitudinal lingual muscle, a transverse lingual muscle, or a vertical lingual muscle.

49. The method of claim 47, wherein the laryngeal muscle is a thyroarytenoid muscle, a vocalis muscle, a lateral cricoarytenoid muscle, a posterior cricoarytenoid muscle, an interarytenoid muscle, a suprahyoid muscle, or an infrahyoid muscle.

50. The method of claim 49, wherein the suprahyoid muscle is a digastric muscle, a stylohyoid muscle, a mylohyoid muscle, or a geniohyoid muscle.

51. The method of claim 49, wherein the infrahyoid muscle is a sternohyoid muscle, a sternothyroid muscle, a thyrohyoid muscle, or omohyoid muscle.

52. The method of claim 47, wherein the pharyngeal muscle is a superior pharyngeal constrictor muscle, a middle pharyngeal constrictor muscle, an inferior pharyngeal constrictor muscle, a palatopharyngeus muscle, a salpingopharyngeus muscle, or a stylopharyngeus muscle.

53. The method of claim 47, wherein the oral cavity muscle is a bilateral mylohyoid muscle, a buccinator muscle, or a geniohyoid muscle.

54. A system for performing microenergy acoustic pulse (MAP) therapy, the system comprising:a MAP generator;a shockwave probe operatively coupled to the MAP generator, wherein the shockwave probe is adapted for positioning at a location to deliver MAP stimulation to a muscle of the upper aerodigestive tract of a subject; anda processor programmed to instruct the shockwave probe to deliver the MAP stimulation to the upper aerodigestive tract of the subject using the shockwave probe in a manner effective to treat a sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder in the subject.

55. The system of claim 54, wherein the shockwave probe is a focused shockwave probe or a radial shockwave probe.

56. The system of claim 54 or 55, wherein the sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder is dysphagia, presbyphonia, a breathing disorder, aspiration pneumonia, or obstructive sleep apnea.

57. The system of claim 56, wherein the shockwave probe is adapted for positioning at a location to deliver MAP stimulation to a genioglossus muscle and a laryngeal muscle for treatment of the obstructive sleep apnea.

58. The system of claim 56, wherein the shockwave probe is adapted for positioning at a location to deliver MAP stimulation to a pharyngeal muscle for treatment of the dysphagia.

59. The system of claim 56, wherein the shockwave probe is adapted for positioning at a location to deliver MAP stimulation to a laryngeal muscle for treatment of the dysphonia.

60. The system of any one of claims 54-59, wherein the shockwave probe is adapted for positioning on the neck of the subject.

61. The system of any one of claims 54-60, wherein the system further comprises a user interface comprising an input electronically coupled to the processor for instructing the shockwaveprobe to deliver MAP stimulation to the subject to treat the sarcopenia-related or myogenic dysfunction-based upper aerodigestive tract disorder.

62. The system of claim 61, wherein the user interface is password protected and is operable by a health care practitioner.

63. The system of claim 62, wherein the user interface is configured to receive input from the health care practitioner for one or more parameters of the MAP stimulation, wherein the one or more parameters are selected from a target region of the upper aerodigestive tract, stimulation duration, number of pulses, pulse length, pulse frequency, energy flux density, and pressure amplitude.

64. The system of any one of claims 54-63, further comprising a storage component for storing data, wherein the storage component is coupled to the processor.

65. The system of any one of claims 54-64, further comprising a display for displaying information about the MAP therapy.

66. The system of claim 65, wherein the display further displays a user interface presenting a questionnaire configured to receive input from the subject regarding self-reported results of treatment with the MAP stimulation.

67. The system of claim 65 or 66, wherein the display further displays a user interface to allow modification of the MAP therapy by a user, wherein the user can change a stimulation pulse pattern or spatial geometry of the MAP stimulation.

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