Systems and methods for treating hearing loss

Abstract

Systems and methods can be employed to access the middle ear through the tympanic membrane for the delivery of therapeutic agents to, for example, the round window niche adjacent to the cochlea under direct visualization. The systems and methods can also be used to improve accessibility and visualization for various otologic procedures, such as, but not limited to, cholesteatoma removal, tympanic membrane repair, and ossicular chain repair.

Description

[0001] Cross-references to related applications

[0002] This application claims U.S. Provisional Application No. 62 / 965,481, filed January 24, 2020; U.S. Provisional Application No. 63 / 024,183, filed May 13, 2020 (which is incorporated herein by reference in its entirety); U.S. Provisional Application No. 63 / 040,495, filed June 17, 2020 (which is incorporated herein by reference in its entirety); U.S. Provisional Application No. 63 / 051,568, filed July 14, 2020 (which is incorporated herein by reference in its entirety); and U.S. Provisional Application No. 63 / 077,481, filed September 11, 2020. Priority interests in 48 (which are fully incorporated herein by reference), U.S. Provisional Application No. 63 / 078,141 filed September 14, 2020 (which are fully incorporated herein by reference), U.S. Provisional Application No. 63 / 080,510 filed September 18, 2020 (which are fully incorporated herein by reference), U.S. Provisional Application No. 63 / 081,015 filed September 21, 2020 (which are fully incorporated herein by reference), and U.S. Provisional Application No. 63 / 082,996 filed September 24, 2020 (which are fully incorporated herein by reference). Technical Field

[0003] This document relates to systems, methods, and materials for treating ear disorders, including but not limited to hearing loss. In some examples, systems and methods include transtympanic access to the middle ear for targeted delivery of therapeutic agents under direct visualization. Background Technology

[0004] The human ear is susceptible to a variety of conditions, including but not limited to hearing loss, tinnitus, balance disorders (including vertigo), Meniere's disease, vestibular neuritis, vestibular schwannoma, labyrinthitis, otosclerosis, ossicular chain dislocation, cholesteatoma, external ear infection, middle ear infection, schwannoma, and tympanic membrane perforation, to provide a few examples.

[0005] In one example, conductive hearing loss (CHL) involves the loss of the normal mechanical pathway for sound to reach the hair cells in the cochlea, such as due to malformation, fluid buildup in the middle ear, damage to the tympanic membrane, the presence of a tumor, and / or damage to the ossicles. Sensorineural hearing loss (SNHL) is caused by the absence or damage of cochlear hair cells or the auditory nerve. SNHL is commonly associated with exposure to loud noise, head trauma, aging, infection, Meniere's disease, tumors, ototoxicity, and genetic disorders such as Usher disease. Summary of the Invention

[0006] This document describes systems and methods for minimally invasive access to the middle ear for the purpose of providing treatment for inner and middle ear conditions. For example, this document describes systems and methods for transtympanic access devices to achieve minimally invasive delivery of a therapeutic agent into the round window niche and adjacent to the round window membrane of the cochlea under direct visualization. In a particular embodiment, the active agent of the therapeutic agent can then be passively transferred to the perilymph (within the cochlea) via diffusion across the round window membrane according to a concentration gradient. The devices, systems, materials, compounds, compositions, articles, and methods described herein can be used to treat a variety of conditions of the middle and / or inner ear, including but not limited to hearing loss, tinnitus, balance disorders including vertigo, Meniere's disease, vestibular neuronitis, vestibular aneurysm, labyrinthitis, otosclerosis, ossicular chain dislocation, cholesteatoma, middle ear infection, and tympanic membrane perforation, to provide several examples.

[0007] Some embodiments described herein include a system for precisely delivering a therapeutic agent to a patient's cochlea. The system may include at least a first tympanic membrane port device and a second tympanic membrane port device, an endoscope, and a syringe device. The first and second tympanic membrane port devices may optionally be configured to be removably implanted in laterally spaced locations within a patient's tympanic membrane. The first tympanic membrane port device may define a first cavity, and the second tympanic membrane port device may define a second cavity. Optionally, when the first tympanic membrane port device is implanted in the tympanic membrane, the endoscope may slide through the first cavity of the first tympanic membrane port device, such that a distal portion of the endoscope can be positioned in the middle ear to visualize the circular window region of the cochlea. Optionally, when the second tympanic membrane port device is implanted in the tympanic membrane, the syringe device may slide through the second cavity of the second tympanic membrane port device, such that a curved distal tip portion of the syringe device can be advanced into the circular window region. The syringe device can be configured to deposit a therapeutic agent at the round window niche, on the round window membrane, directly into the cochlea, or into other parts of the middle ear cavity; while the distal portion of the endoscope (optionally) is laterally spaced from the syringe device in the middle ear to provide visualization of the syringe device.

[0008] Additional embodiments described herein include a system for injecting an ototherapy fluid into a circular window niche adjacent to a patient's cochlea. The system may include an inner ear injection device and an ototherapy fluid source. The inner ear injection device may include a proximal portion and a flexible distal tip portion. Optionally, the flexible distal tip portion may be adjusted from a longitudinally straight shape during advancement through the patient's tympanic membrane to a curved shape to orient the distal delivery port of the distal tip portion at the circular window of the cochlea. Furthermore, the ototherapy fluid source may be in fluid communication with the inner ear injection device such that the distal delivery port of the distal tip portion is configured to deposit the ototherapy fluid into the circular window niche, while the flexible distal tip portion is arranged in a curved shape.

[0009] In certain embodiments, the system may include a tympanic membrane port device having access to the inner cavity. Additionally, the system may optionally include an inner ear tissue manipulator having a tissue-engaging tip portion movable within the middle ear to modify a pseudomembrane that at least partially covers the inner ear's circular window. In such embodiments, the inner ear tissue manipulator may have a first axial diameter configured to occupy a majority of the inner cavity of the tympanic membrane port device and may be shaped to advance through the inner cavity of the tympanic membrane port device within the tympanic membrane. The system may also optionally include an inner ear medication injector having a steerable distal tip portion configured to enter the circular window region where the pseudomembrane has been modified and to deposit medication into a circular window niche adjacent to the circular window membrane of the cochlea. In such embodiments, the inner ear medication injector may have a second axial diameter configured to occupy a majority of the inner cavity of the tympanic membrane port device and may be shaped to advance through the same tympanic membrane port device.

[0010] Other embodiments described herein include methods for treating hearing loss in a patient. Optionally, the method may include advancing a puncture needle carrying a first tympanic membrane port device into the patient's outer ear, and using the distal tip portion of the puncture needle to form a first puncture opening in the patient's tympanic membrane while the puncture needle carries the first tympanic membrane port device. Furthermore, the method may include advancing the distal tip portion of the puncture needle through the puncture opening to implant the first tympanic membrane port device into the tympanic membrane, and the first tympanic membrane port device may define a first cavity through which it passes. Optionally, the method may include advancing a syringe instrument into the patient's outer ear and the first cavity until the port defined by the distal tip of the syringe instrument is close to the round window niche of the patient's cochlea. Furthermore, the method may include injecting a therapeutic fluid via the syringe instrument into the round window niche of the round window membrane adjacent to the cochlea. The therapeutic fluid may reside as a gel substance in the patient's round window niche.

[0011] The additional embodiments described herein include a system comprising: a middle ear visualization device deliverable through the tympanic membrane and having a distal end positionable in the middle ear to visualize the circular window niche of the cochlea; and a therapeutic device deliverable through the tympanic membrane to a location spaced apart from the middle ear visualization device. The therapeutic device may be configured to treat at least one of the following: hearing loss, tinnitus, balance disorder, vertigo, Meniere's disease, vestibular neuronitis, vestibular neuroma, labyrinthitis, otosclerosis, ossicular chain dislocation, cholesteatoma, middle ear infection, and tympanic membrane perforation. In some embodiments, the system further includes at least one tympanic membrane port device insertable into the tympanic membrane to define transtympanic access into the endocardium.

[0012] Some or all of the embodiments described herein may offer one or more of the following advantages. First, systems and methods for treating hearing loss and all other ear conditions as described herein may include specialized techniques and instruments for accessing the round window niche of the cochlea and precisely delivering a therapeutic preparation that is a gel or has turned into a gel. Compared to liquid therapeutic preparations that are easily expelled from the cochlea, a gel-formed therapeutic preparation advantageously remains located in the round window membrane adjacent to the cochlea for a longer period, during which time the active ingredient of the therapeutic preparation can be gradually released into the perilymph (within the cochlea). Compared to liquid therapeutic preparations, gel-formed therapeutic preparations in some cases require precise placement in the round window niche to avoid affecting the mobility of middle ear structures (such as ossicles), which can lead to temporary but severe conductive hearing loss. This sustained release of the active ingredient thus advantageously reduces the frequency of reapplication of the therapeutic preparation. Furthermore, due to the longer middle ear residence and increased diffusion into the inner ear, the overall therapeutic efficacy provided by applying a gel-formed therapeutic preparation tends to be better than that provided by applying a liquid-formed therapeutic preparation. Systems and methods for treating hearing loss and all other ear conditions as described herein may also include specialized techniques and instruments for accessing the round window niche of the cochlea and precisely placing solid implants or continuous delivery systems on or across the round window membrane, or for delivering therapeutic treatments directly into the perilymph across the round window membrane. Systems and methods for treating hearing loss and all other ear conditions as described herein may also include specialized techniques and instruments for precisely delivering therapeutic drugs to other parts of the middle ear cavity.

[0013] Secondly, the systems and methods described herein for treating hearing loss deliver the therapeutic agent into the cochlea under direct visualization. This use of direct visualization advantageously allows for visual confirmation, with a high level of precision, of the proper placement of the therapeutic agent at the round window niche of the cochlea. Direct visualization also provides additional benefits, such as the ability to visually determine the presence of any obstructions at the round window that could inhibit the proper delivery of the therapeutic agent. For example, in some cases, the round window is covered by a dummy membrane, which can be altered or moved to allow improved access to the round window niche. By using the improved instruments described herein, the presence of the dummy membrane can be visually verified, and subsequently physically altered or moved, enabling visual verification of improved and direct access to the round window niche. Furthermore, after the therapeutic agent has been administered adjacent to the round window of the cochlea, direct visualization can be used to verify that the therapeutic agent remains in the desired position and in the desired manner.

[0014] Third, the systems and methods described herein for treating hearing loss and other ear conditions allow for direct access to the middle ear cavity through the tympanic membrane in a seamless, low-impact manner. In some embodiments, this direct access through the tympanic membrane using a tympanic membrane port device can be safer and less invasive, and can be achieved without sealing or repair after removal of the tympanic membrane port device. For example, due to the smaller size of the tympanic membrane port device, the tympanic membrane can heal naturally after removal of the tympanic membrane port device.

[0015] Fourth, the systems and methods described herein for treating hearing loss and other ear conditions promote minimally invasive treatment. Such minimally invasive techniques tend to reduce recovery time, patient discomfort, and treatment costs. Furthermore, the methods described herein can be performed using local anesthetics without requiring general anesthesia. Therefore, treatment costs, patient risks, and recovery time are further advantageously reduced.

[0016] Fifth, the system described in this article can also be used for diagnostic purposes. These uses can aid in surgical planning, modify care sites, and potentially improve patient outcomes.

[0017] Sixth, the systems and methods described herein facilitate transtympanic or other visualization of the middle ear, which can then be used to diagnose interference with middle ear structures, locate middle ear structures, locate structures at the junction with the inner ear, and guide instruments or therapeutic drugs into the desired structures in the middle or inner ear.

[0018] Seventh, some of the systems and methods described in this article facilitate the entry of instruments or visualization tools into the middle or inner ear via the tympanic membrane, while simultaneously providing local reinforcement of the tympanic membrane. This is advantageous as a means of reducing tympanic membrane tears or damage during diagnostic or therapeutic interventions, when manipulating visualization or entry instruments.

[0019] Eighth, some of the systems and methods described in this article facilitate the entry of instruments or visualization tools into the middle or inner ear while reducing pain or injury to the ear canal walls and tympanic membrane. Pain and discomfort associated with ear canal-based surgeries often necessitate increased levels of anesthesia or sedation, which increases the demand for specialists, equipment, and surgical facilities. Damage to the ear canal walls, due to their extensive vascularization, is associated with frequent and high rates of bleeding, which can slow down or increase the difficulty of the procedure, requiring additional instrumentation and therapeutic interventions.

[0020] Ninth, some of the systems and methods described herein facilitate the entry of instruments or visualization tools into the middle or inner ear while providing stability or fixation against external ear structures or the tympanic membrane.

[0021] Tenth, some of the systems and methods described herein facilitate the healing, resealing, or closure of the tympanic membrane after penetration or other perforation or damage to the tympanic membrane.

[0022] Details of one or more embodiments of the invention are set forth in the accompanying drawings and the description below. Other features, objects, and advantages of the invention will become apparent from the specification, drawings, and claims. Attached Figure Description

[0023] Figure 1 This is a schematic diagram of a medical procedure for treating hearing loss according to some embodiments.

[0024] Figure 2 Showing according to Figure 1 A perspective view of the therapeutic gel material residing in the cochlea delivered through the round window of the cochlea during surgery.

[0025] Figure 3 A perspective view of an exemplary tympanic membrane port device mounted on a delivery puncture device according to some embodiments is shown.

[0026] Figure 4 Show Figure 3 A perspective view of the tympanic membrane port device.

[0027] Figure 5 The illustration shows a perspective view of an exemplary endoscopic instrument with a distal viewing tip configured to... Figure 3 The tympanic membrane port device is pushed into the middle ear.

[0028] Figure 6 A perspective view is shown of a membrane modification device configured as an exemplary membrane modification device, which is transmitted via... Figure 3 The tympanic membrane port device is pushed into the middle ear.

[0029] Figure 7 A perspective view of an exemplary therapeutic agent injection device is shown, the exemplary therapeutic agent syringe device being configured to... Figure 3 The tympanic membrane port device is pushed into the middle ear.

[0030] Figure 8 The patient is shown in the position described in this article during a medical procedure to treat hearing loss and other ear conditions.

[0031] Figure 9 The protective sheath is shown being inserted into the patient's outer ear and advanced toward the patient's tympanic membrane.

[0032] Figure 10 The image shows the puncture of the patient's tympanic membrane and the placement of the tympanic membrane port device within the patient's tympanic membrane.

[0033] Figure 11 A device with two tympanic membrane ports implanted in a patient's tympanic membrane is shown.

[0034] Figure 12 A perspective view of the sheath of the tympanic membrane delivery port device is shown.

[0035] Figure 13 It shows Figure 12 A perspective view of a protective sheath having a tympanic membrane port device and a delivery puncture device extending distally from the sheath.

[0036] Figure 14 It shows Figure 13 A perspective view of the device in which the needle for delivering the puncture device is retracted proximally.

[0037] Figure 15 Showing separation from the sheath and delivery trocar Figure 13 A perspective view of the tympanic membrane port device.

[0038] Figure 16 The device shows two tympanic membrane ports in the patient's tympanic membrane (according to...) Figure 11 (and an exemplary endoscope device extending through the first of the tympanic membrane port devices.)

[0039] Figure 17 It shows Figure 16 The arrangement, wherein the exemplary tweezers device extends through the second of the tympanic membrane port devices.

[0040] Figure 18 It shows Figure 17 The forceps device extends toward the pseudomembrane covering the circular window of the patient's cochlea.

[0041] Figure 19 It shows Figure 17 The tweezers device grasps a portion of the dummy membrane and pulls it to create an open entrance to the circular window.

[0042] Figure 20 The device shows two tympanic membrane ports in the patient's tympanic membrane (according to...) Figure 11 (and an exemplary endoscope device extending through the first of the tympanic membrane port devices.)

[0043] Figure 21 It shows Figure 20 The arrangement, wherein the exemplary suction pickup device extends through a second tympanic membrane port device.

[0044] Figure 22 It shows Figure 21 The suction pickup device extends toward the pseudomembrane covering the circular window of the patient's cochlea.

[0045] Figure 23 It shows Figure 21 The suction pickup device pulls a portion of the dummy membrane to create an open inlet leading to the circular window.

[0046] Figure 24 The device shows two tympanic membrane ports in the patient's tympanic membrane (according to...) Figure 11 (and an exemplary endoscope device extending through the first of the tympanic membrane port devices.)

[0047] Figure 25 It shows Figure 24 The arrangement, wherein the exemplary tissue expander device extends through the second of the tympanic membrane port devices.

[0048] Figure 26 It shows Figure 25 The tissue expander device extends toward the pseudomembrane covering the circular window of the patient's cochlea.

[0049] Figure 27 It shows Figure 25 A tissue expander device that separates a portion of the pseudomembrane to create an open inlet leading to a circular window.

[0050] Figure 28 An exemplary endoscope device is shown that extends through an exemplary tympanic membrane port device.

[0051] Figure 29 An exemplary forceps device is shown that extends through an exemplary tympanic membrane port device. The forceps device is shown in an open configuration.

[0052] Figure 30 An exemplary forceps device is shown that extends through an exemplary tympanic membrane port device. The forceps device is shown in a closed configuration.

[0053] Figure 31 An exemplary suction pickup device is shown that extends through an exemplary tympanic membrane port device.

[0054] Figure 32 An exemplary tissue expander device is shown that extends through an exemplary tympanic membrane port device.

[0055] Figure 33 Another exemplary tissue expander device is shown, extending through an exemplary tympanic membrane port device.

[0056] Figure 34 The device shows two tympanic membrane ports in the patient's tympanic membrane (according to...) Figure 11 An exemplary endoscope device extending through the first of the tympanic membrane port devices and an exemplary injection device extending through the second of the tympanic membrane port devices.

[0057] Figure 35 It shows Figure 34 The injection device extends and is oriented in preparation for injecting a therapeutic agent into the round window of the patient's cochlea.

[0058] Figure 36 It shows Figure 34 The injection device delivers a dose of therapeutic agent into the round window of the patient's cochlea.

[0059] Figure 37 An exemplary light energy delivery device is shown that projects light energy onto a therapeutic agent to photocur the therapeutic agent into a gel.

[0060] Figure 38 An exemplary injection device is shown, which extends through an exemplary tympanic membrane port device and is in a first configuration.

[0061] Figure 39 It shows Figure 38 The injection device extends through an exemplary tympanic membrane port device and is in a second configuration.

[0062] Figure 40 It shows Figure 38 The injection device extends through an exemplary tympanic membrane port device and is in a third configuration.

[0063] Figure 41 Another exemplary injection device is shown, extending through an exemplary tympanic membrane port device.

[0064] Figure 42 An exemplary cross-section of the extendable injection tube of the injection device of claim 41 is shown.

[0065] Figure 43 An exemplary therapeutic agent supply device is shown that is coupled to the injection device of claim 41.

[0066] Figure 44 This is a flowchart of an exemplary method for treating hearing loss according to some embodiments.

[0067] Figure 45 An exemplary otological instrument is shown with an optional movable sleeve device that defines a working channel coupled to the axis of the instrument.

[0068] Figure 46 Show Figure 45 An exemplary cross-sectional view of a removable sleeve device.

[0069] Figure 47 Show Figure 45 Another exemplary cross-sectional view of the removable sleeve device.

[0070] Figure 48 Show Figure 45 Another exemplary cross-sectional view of the removable sleeve device.

[0071] Figure 49The right tympanic membrane is shown with overlapping lines and markings indicating the coordinates of the position around the tympanic membrane ring.

[0072] Figure 50 An exemplary tympanic membrane port device including an anchoring portion is shown.

[0073] Figure 51 It shows having Figure 50 The tympanic membrane and tympanic membrane ring are two tympanic membrane port devices.

[0074] Figure 52 A tympanic membrane and tympanic membrane ring with an exemplary dual-port tympanic membrane port device are shown.

[0075] Figure 53 A tympanic membrane and tympanic membrane ring are shown, which have another exemplary dual-port tympanic membrane port device.

[0076] Figure 54 A tympanic membrane and tympanic membrane ring with an exemplary three-port tympanic membrane port device are shown.

[0077] Figure 55 An exemplary endoscopic instrument is shown.

[0078] Figure 56 Showing a liquid lens Figure 55 An exemplary tip portion of an endoscopic instrument.

[0079] Figure 57 Another one with a liquid lens is shown. Figure 55 An exemplary tip portion of an endoscopic instrument.

[0080] Figure 58 This is a schematic diagram of a system designed to facilitate minimally invasive access to the middle ear for the purposes of diagnosing middle ear disorders, planning surgeries, and delivering treatments for inner and middle ear conditions.

[0081] Figure 59 Side and front views of a tympanic membrane according to some embodiments are shown, the tympanic membrane having one or more membrane support structures adjacent to the tympanic membrane, the one or more membrane support structures being for use with... Figure 58 Used together with the system.

[0082] Figure 60 A side view of a tympanic membrane having one or more external support structures according to some embodiments is shown, the one or more external support structures being used to... Figure 58 Used together with the system.

[0083] Figure 61 Showing according to Figure 58 A side view of the tympanic membrane subjected to middle ear inflation in some embodiments of the system.

[0084] Figure 62 and63 A cross-sectional view of an exemplary endoscope axis is shown.

[0085] Figure 64 The distal portion of an exemplary endoscope axis is shown.

[0086] Figure 65 An exemplary working channel of an endoscope is shown.

[0087] Figures 66-68 The distal portion of another exemplary endoscope is shown.

[0088] Figure 69 and 70 The distal portion of another exemplary endoscope is shown.

[0089] Figure 71 The distal portion of another exemplary endoscope is shown.

[0090] Figure 72 and 73 An exemplary stabilizing device is shown.

[0091] Figure 74 Another exemplary stabilizing device is shown.

[0092] Figure 75 Another exemplary stabilizing device is shown.

[0093] Figure 76 and 77 An exemplary arrangement for simultaneously acquiring two endoscopic images is shown.

[0094] Figure 78 and 79 Exemplary devices for delivering substances and for suction are shown.

[0095] The same reference numerals in the various figures denote the same elements. Detailed Implementation

[0096] Now for reference Figure 1-2 Specific embodiments of the systems and methods for treating patient 10 may include a set of improved medical devices for, for example, delivering a therapeutic agent 100 to a target site at the cochlea 50 of patient 10 under direct endoscopic visualization. The devices, systems, and methods described herein can be used to treat and / or prevent a variety of conditions, including but not limited to hearing loss, including latent hearing loss, noise-induced hearing loss, age-related hearing loss, drug-induced hearing loss (e.g., chemotherapy-induced hearing loss or aminoglycoside-induced hearing loss), sudden sensorineural hearing loss (SNHL), autoimmune inner ear diseases, cholesteatoma, etc.

[0097] While this article describes devices, systems, materials, compounds, compositions, articles, and methods primarily in the context of treating hearing loss, it should be understood that devices, systems, materials, compounds, compositions, articles, and methods may also be used to treat any other conditions of the middle and / or inner ear, including but not limited to tinnitus, balance disorders including vertigo, Meniere's disease, vestibular neuronitis, vestibular auricular tumor, labyrinthitis, otosclerosis, ossicular chain dislocation, cholesteatoma, middle ear infection, and tympanic membrane perforation, to provide a few examples.

[0098] This disclosure describes treatment methods and devices for treating patient 10 using minimally invasive methods. For example... Figure 1 As shown, a clinician 1 approaches the cochlea 50 through the external auditory canal 20 of a patient 10 using various instruments (collectively referred to herein as general instrument 110) as further described below. Instrument 110 is advanced through the tympanic membrane (TM) 30 via one or more temporarily implanted tympanic membrane port devices 200. The distal portion of instrument 110 is thus advanced toward the round window 52 of the cochlea 50 into the middle ear 40.

[0099] As described in more detail below, the system's apparatus can be configured to deliver therapeutic agent 100 to the circular window niche 52 and adjacent to the circular window membrane of the cochlea 50. The active ingredient of the therapeutic agent 100 then passively moves through the membrane of the circular window 52 by diffusion according to a concentration gradient and enters the perilymph (within the cochlea 50). In some embodiments, the therapeutic agent 100 delivered adjacent to the circular window membrane of the cochlea 50 may subsequently reside as a semi-solid gel material near or within the slit of the circular window 52. As a gel material, the delivery of the therapeutic agent 100 will be maintained at the target site at the cochlea 50, such that the therapeutic agent 100 can gradually release its active ingredient over an extended period of time (e.g., days, weeks, or even months).

[0100] After delivery of the therapeutic formulation 100, the device 110 and one or more TM port devices 200 can be removed from the patient 10. The TM port devices 200 can be sized and shaped such that the opening of the TM 30 (in which the TM port devices 200 are positioned) can heal naturally (without sutures). The therapeutic formulation 100 (e.g., in gel form) will remain at the target site in the cochlea 50 to provide a prolonged therapeutic effect through controlled and sustained release of the active ingredient into the body of the patient 10.

[0101] Sustained release can encompass the sustained release of an effective amount of the active ingredient of the therapeutic formulation 100 for an extended period of time. Sustained release can encompass the first-order release of the active ingredient, the zero-order release of the active ingredient, or other release kinetics, such as intermediate stages between zero and first orders, or combinations thereof. Sustained release can also encompass the controlled release of the active ingredient of the therapeutic formulation 100 via passive molecular diffusion driven by a transmembrane concentration gradient or porous structure.

[0102] The procedure for delivering therapeutic agent 100 into the cochlea 50 of patient 10 may be repeated periodically as needed for the specific patient's treatment. For example, in some cases, the therapeutic agent 100 may be delivered approximately every 3 to 24 months, each time using a new TM port device 200 and delivery instrument as described herein. In certain cases, patient 10 may be evaluated to determine whether or when to administer more therapeutic agent 100. In some cases, procedures such as magnetic resonance imaging (MRI) (or other types of procedures) may be performed to aid in such evaluation.

[0103] Also refer to Figure 3-7 Exemplary systems (or kits) of devices and instruments that can be used to perform surgeries for the treatment of hearing loss and other ear conditions as described herein may include one or more of the following: (i) a TM port inserter 220, (ii) one or more TM port devices 200, (iii) an endoscope 300 (or other direct visualization instrument) sized to fit through the TM port device 200, (iv) forceps 400 (or other types of tissue manipulator devices as further described below) sized to fit through the TM port device 200, and (v) a syringe instrument 800 sized to fit through the TM port device 200 and (optionally) including a steerable distal tip. Other types of instruments may optionally include, for example, but not limited to, cannulas, scrapers (single-end or double-end), lifters, forceps, hooks, Luer lock connectors, needles, picks, scalpels, files, retractors, scissors, speculum, suction tubes, tissue forceps, side-biting scissors, and combinations thereof. Some instruments are deflectable or steerable. Some instruments may include suction, flushing, etc. In some embodiments, depth markers are included on the axis of the instrument.

[0104] Endoscope 300, forceps 400, and syringe device 800 are configured to enter the middle ear 40 through TM port device 200, with each TM port device 200 temporarily implanted in the TM 30 of patient 10. That is, the distal portion of at least one of the endoscope 300, forceps 400, and syringe device 800 is configured to slidably pass through the lumen 202 defined by the TM port device 200, which is removably implanted in the TM 30. Where the endoscope 300, syringe device 800, or any other instrument has a different diameter or profile, the TM port device 200 may have different sizes or shapes to accommodate accordingly. In some embodiments further described below, when clinician 1 manipulates another instrument (e.g., forceps 400 or syringe device 800) in the middle ear 40 to perform treatment for hearing loss and other ear conditions as described herein, clinician 1 uses endoscope 300 (when its distal portion is positioned in the middle ear 40) to obtain direct visualization.

[0105] During use, the proximal portion of each of the depicted devices remains outside the patient 10 and can be operated / controlled by the clinician 1. Each of the devices, TM port device 200, and therapeutic agent 100 is further described below.

[0106] Also refer to Figure 8 Patient 10 is depicted in an exemplary suitable position and orientation for receiving surgery to treat hearing loss and other ear conditions as described herein. In some cases, the surgery may be performed with patient 10 fully supine (as shown) or reclining in a chair.

[0107] The patient 10's head can be rotated to approximately 30 to 45 degrees away from the clinician 1 (towards the patient 10's opposite ear). The patient 10's jaw can be slightly raised, and / or the external portion of the patient 10's ear can be pulled upwards and backwards to adjust the ear canal opening and angle. In this way, the patient's round window 52 will be oriented generally upwards (e.g., away from the ground), such that when the treatment preparation 100 is dispensed from the delivery device, the treatment preparation 100 can converge at the round window 52 and not flow toward the Eustachian tube or ossicular chain.

[0108] In some implementations, patient 10 remains conscious during the procedure. That is, a local anesthetic may be used instead of a general anesthetic to perform the procedure. For example, in some cases, a reagent such as phenol or lidocaine may be applied to TM30 as a local anesthetic to facilitate the procedure. In some cases, patient 10 may be given general anesthesia for the procedure.

[0109] refer to Figure 9After preparing patient 10 for surgery, as part of the procedure to temporarily implant the TM port device 200 into the TM 30, the TM port inserter 220 may be advanced toward the TM 30 into the external auditory canal 20. In some cases, when the TM port inserter 220 is advanced and used to insert the TM port device 200 into the TM 30, an endoscope (not shown) is used in the external auditory canal 20 to provide direct visualization of the TM port inserter 220. In some cases, when the TM port inserter 220 is advanced and used to implant the TM port device 200 into the TM 30, a microscope or other magnifying instrument is used to provide direct visualization of the TM port inserter 220.

[0110] Also refer to Figure 12-15 An exemplary TM port inserter 220 includes an elongated delivery sheath 222, a pusher catheter 224, and a puncture needle 226. The pusher catheter 224 is slidably disposed within a lumen defined by the delivery sheath 222. The puncture needle 226 is slidably disposed within a lumen defined by the pusher catheter 224. In a particular embodiment, the pusher catheter 224 and the puncture needle 226 are combined as a single instrument.

[0111] When the TM port device 200 is operably loaded onto the TM port inserter 220 (e.g., Figure 13 The TM port device 200 is releasably coupled to the puncture needle 226, abutting against the distal end of the pusher catheter 224, and slidably disposed within the lumen of the delivery sheath 222. That is, at least the distal portion of the puncture needle 226 is slidably disposed within the lumen 202 of the TM port device 200. In some embodiments, a clearance fit is used between the outer diameter of the distal portion of the needle 226 and the inner diameter of the lumen 202 of the TM port device 200. In a particular embodiment, a slight interference fit is used between the outer diameter of the distal portion of the needle 226 and the inner diameter of the lumen 202 of the TM port device 200.

[0112] When the TM port device 200 is connected to the puncture needle 226, the distal face of the pusher catheter 224 abuts (or may abut) the proximal face of the TM port device 200. Therefore, during or in order to disconnect the TM port device 200 from the puncture needle 226 (and from the integral TM port inserter 220), the pusher catheter 224 can apply a distal force to the TM port device 200. Simply put, the pusher catheter 224 can be used to push the TM port device 200 distally away from the puncture needle 226. Alternatively, that is, when the puncture needle 226 is pulled proximally from the lumen 202 of the TM port device 200, the pusher catheter 224 can resist a proximal force from the TM port device 200.

[0113] The TM port device 200 is slidably disposed within the cavity of the delivery sheath 222. That is, the TM port device 200 can be removably housed within the cavity of the delivery sheath 222 (e.g., Figure 12 In this arrangement, the TM port device 200 is not visible because it is located inside the delivery sheath 222. This arrangement can be used, for example, in situations such as... Figure 9 During the advancement of the TM port inserter 220 within the external auditory canal 20, the TM port inserter 220 is loaded with the TM port device 200.

[0114] An exemplary TM port device 200 includes three contiguous portions: (i) a distal portion 204, (ii) a middle portion 206, and (iii) a proximal portion 208. A lumen 202 centrally passes through each of portions 204 / 206 / 208. In some embodiments, the diameter of the lumen 202 is in the range of 0.4 mm to 0.6 mm, 0.5 mm to 0.75 mm, or 0.5 mm to 1.0 mm, but is not limited thereto.

[0115] The inner diameter or cavity of the proximal portion 208 may be tapered to have a larger diameter at the proximal end, thereby forming a funnel shape to facilitate alignment of the instrument when it enters the port device.

[0116] The distal portion 204 may be truncated conical in shape. That is, the outer diameter of the farthest end of the distal portion 204 is smaller than the nearest end of the distal portion 204. The intermediate portion 206 and the proximal portion 208 are each cylindrical. The outer diameter of the intermediate portion 206 is smaller than the outer diameters of (i) the nearest end of the distal portion 204 and (ii) the proximal portion 208. Therefore, in this embodiment, the intermediate portion 206 can be considered as the “waist region” of the TM port device 200. The cavity 202 may be conical, cylindrical, elliptical, pyramidal, or other shapes, as may the distal portion 204.

[0117] As further described below, when the TM port device 200 is implanted in the TM 30, the intermediate portion 206 is the site where tissue of the TM 30 will reside (at least primarily). The relatively small outer diameter of the intermediate portion 206 (compared to the outer diameters of adjacent portions of the distal portion 204 and the proximal portion 208) will facilitate the retention of the TM port device 200 in the TM 30. In some embodiments, the outer diameter of the intermediate portion 206 is in the range of 0.25 mm to 0.75 mm, 0.25 mm to 1.0 mm, or 0.5 mm to 1.25 mm, but is not limited thereto. The longitudinal length of the intermediate portion 206 may be in the range of 0.1 mm to 0.3 mm, 0.1 mm to 0.5 mm, or 0.2 mm to 0.6 mm, but is not limited thereto. The outer diameter and length of the intermediate portion 206 are sufficient to receive the thickness of the TM 30 while preventing unintentional application of buckling, tearing, or other forces to the TM 30 during insertion of the TM port device 200. In some embodiments, the lumbar region is excluded, and the frictional engagement between the distal portion and the TM is sufficient to hold the port device in the TM for the duration of the procedure while reducing the forces exposed to the TM during port insertion or removal.

[0118] In some embodiments, the TM port device 200 can be implanted in the TM 30 without the use of a puncture needle. Instead, the incision in the TM 30 can be made first using a blade, needle, or laser. The TM port device 200 can then be implanted into the TM 30 by advancing the TM port device 200 into the incision.

[0119] When the TM port device 200 is implanted (or attached, connected, joined, etc.) to the TM30, the TM port device 200 serves as a retaining ring, a stress-relieving component to prevent tearing of the TM30, a middle ear inlet port, an instrument insertion channel, a working channel, etc.

[0120] The TM port device 200 is configured and sized such that removal of the TM port device 200 from the TM 30 does not require the use of sutures to seal any incision or opening formed in the TM 30 during insertion of the TM port device 200. Typically, the length of the self-sealing opening through the TM 30 is no greater than about 2.5 mm, preferably between about 0.5 mm and 1.5 mm. While the tools and methods described herein offer the advantage of seamless access to the middle ear and / or inner ear, this does not preclude the surgeon from applying one or more closure techniques after removal of the TM port device 200. That is, one or more techniques for closing the opening in the TM 30 may be performed if the clinician wishes.

[0121] The TM port device 200 may be formed of a material with rigidity and strength for insertion and removal from the TM 30, while also withstanding stresses that may occur during manipulation of the inserted surgical instrument. In some embodiments, at least a portion of the TM port device 200 is formed of a surgical metal (e.g., stainless steel, titanium, platinum, nitinol) and / or a plastic (e.g., polyimide, PEEK, fluoropolymer, silicone, etc.). In some embodiments, the insertion portion of the TM port device 200 may be formed of polyimide (or other rigid or semi-rigid polymer) and have a maximum outer diameter not exceeding about 20 gauges (0.8 mm). One or more portions of the TM port device 200 may be coated with or formed of an elastic conformal material. For example, the retaining feature 102 may be coated with a material such as silicone or polyurethane or formed by overmolding using a material such as silicone or polyurethane.

[0122] Still referencing Figure 9 In preparation for implantation of the TM port device 200 into the TM30, the TM port inserter 220, which internally houses the TM port device 200, is advanced into the external auditory canal 20 toward the TM30. During advancement, the TM port inserter 220 can be configured as follows: Figure 12 The pusher catheter 224, puncture needle 226 and TM port device 200 are all located inside the lumen of the delivery sheath 222.

[0123] refer to Figure 10 When the delivery sheath 222 has been advanced within the external auditory canal 20 to the point where the distal end of the delivery sheath 222 is adjacent to the TM 30, the pusher catheter 224, the puncture needle 226, and the TM port device 200 can then extend distally from the interior of the delivery sheath 222 (e.g., Figure 13 (As shown). Because the distal tip of the puncture needle 226 is configured to puncture the TM30 with an angled, sharp tip, the distal tip of the puncture needle 226 can puncture the TM30. As the pusher catheter 224 (optionally and the puncture needle 226) extends further, the distal portion 204 of the TM port device 200 ( Figure 15 This will enter and expand (dilate) the puncture initially created by the puncture needle 226 into the TM30. Further advancement will position the intermediate portion 206 of the TM port device 200 to remain engaged with the TM30. Thus, as Figure 15 As shown, the TM port inserter 220 can be retracted from the TM port device 200, leaving the TM port device 200 releasably connected to the TM 30.

[0124] refer to Figure 11One or more TM port devices 200 may be removably implanted in TM 30. When implanted, the proximal portion 208 of the TM port device 200 is located in the external auditory canal 20, the distal portion 204 of the TM port device 200 is located in the middle ear 40, and the intermediate portion 206 of the TM port device 200 receives tissue from TM 30. When implanted, the lumen 202 of the TM port device 200 defines an open passage between the external auditory canal 20 and the middle ear 40. In some embodiments, the passage of the TM port device 200 between the external auditory canal and the middle ear may include friction elements, valves, or other elements to regulate the movement of an instrument, gas, or liquid through the passage of the TM port device 200.

[0125] As depicted, in some embodiments, two of the TM port devices 200 are temporarily embedded in the TM 30. In this case, the two TM port devices 200 may be laterally spaced apart from each other while embedded in the TM 30 (e.g., laterally spaced apart relative to an axis defined by the channel of the TM port device 200). In some embodiments, the two TM port devices 200 are laterally spaced apart from each other at a distance ranging from 0.5 mm to 8 mm while embedded in the TM 30.

[0126] refer to Figure 16 The TM port device 200 is implanted in the TM 30 to provide an inlet for an instrument (e.g., the depicted endoscope 300), allowing the instrument to extend through and into the middle ear 40. The axis of the endoscope 300 has a lumen 202 smaller than that of the TM port device 200. Figure 15 The outer diameter of the endoscope 300 is the diameter of the endoscope 202. Therefore, the endoscope 300 is slidably positioned through the lumen 202. When the endoscope 300 extends through the TM port device 200 as shown, the distal portion 310 of the endoscope 300 is positioned in the middle ear 40, allowing visualization of the cochlea 50 (including the niche of the circular window 52) within the middle ear 40. For example, in... Figure 28 As shown, the distal portion 310 of the endoscope 300 can emit visible light and receive images. In some embodiments, the endoscope 300 includes a bundle of optical fibers that conducts light from a light source outside the patient 10 to the distal portion 310 of the endoscope 300. In a particular embodiment, one or more light sources (e.g., one or more light-emitting diodes) may be located in the distal portion 310. The light emitted from the distal portion 310 illuminates the field of vision within the middle ear 40 of the patient 10.

[0127] In some embodiments, as an alternative to, or additionally to, a light source positioned distal to the endoscope 300, may be positioned outside the TM30 (in the external auditory canal 20) to increase the user's ability to view the instrument through the translucent aspect of the TM30 under illumination. This externally positioned light source can be used to illuminate the field of view within the middle ear 40 of the patient 10. In some such embodiments, an endoscope without a light source may be used in the middle ear 40 (while the middle ear 40 is illuminated by a light source positioned in the ear canal outside the TM30). In a particular embodiment, the distal end of the endoscope may be located in the external auditory canal 20 near the TM30, such that the camera (or another type of camera) of the endoscope 300 may alternatively be positioned outside the TM30. In this case, a camera positioned outside the TM30 (in the external auditory canal 20) can be used to provide enhanced visibility through the translucent aspect of the TM30 (under illumination) and into the middle ear 40. Therefore, in some cases, only a single TM port device 200 is implanted in the TM30 to perform surgery as described herein for treating ear conditions.

[0128] In some embodiments, as an alternative to, or additional to, a chandelier-type light source (not shown) may be positioned in the middle ear 40 to illuminate the middle ear 40 in an ambient manner. In some such embodiments, an endoscope without a light source may be used in the middle ear 40 (while the middle ear 40 is illuminated by a chandelier-type light source positioned in the middle ear 40).

[0129] Optionally, in some embodiments, the TM port device 200 may be enhanced to include visualization features. For example, in some embodiments, the TM port device 200 may be formed wholly or at least partially of a light-transmitting material, such that the TM port device 200 can receive light at its proximal side and transmit light through it for emission from the distal side and into the middle ear. In this case, a light source (e.g., fiber optic, LED, etc.) may be coupled to the outer wall of the TM port device 200 (e.g., at the proximal side). Light can thus be conducted into the middle ear 40 through the light-transmitting TM port device 200. In some cases, the light source may be positioned outside the TM 30 (in the external auditory canal 20), and the TM port device 200 may conduct light into the middle ear 40. Furthermore, in some embodiments, the TM port device 200 may be enhanced to include a camera (or be connectable to a camera) in the sidewall of the port device 200 to maintain the availability of the central cavity for receiving other instruments. Thus, in some cases, only a single TM port device 200 is implanted in the TM 30 to perform surgery as described herein for treating ear conditions.

[0130] Additionally, in some embodiments, endoscope 300 includes a second fiber optic bundle that transmits images received at the distal portion 310 to a viewing system outside the patient. The images are then displayed at the viewing system for use by clinician 1. In a particular embodiment, a miniature camera (e.g., CCD-based) is located at the distal portion 310. In some embodiments, a lens is included at the distal portion 310. In a particular embodiment, endoscope 300 is a high-resolution wide-field endoscope. In some embodiments, endoscope 300 is steerable or deflectable in one or more planes. In any case, using endoscope 300, which is slidably disposed through the lumen 202 of TM port device 200, clinician 1 can directly visualize at least the area of ​​the patient's cochlea 50 and round window 52 during the performance of surgery to treat hearing loss and other ear conditions as described herein. In some embodiments, endoscope 300 defines one or more working channels through which instruments can be advanced and used.

[0131] refer to Figure 17 While the endoscope 300 is slidably disposed through the first of the TM port devices 200, another instrument is slidably disposed through the second of the TM port devices 200. In the depicted arrangement, forceps 400 are disposed through the second of the TM port devices 200. The distal portion 410 of the forceps 400 can thus be positioned within the middle ear 40.

[0132] Also refer to Figure 29 and Figure 30 The distal portion 410 of the forceps 400 may include a gripping mechanism. In the depicted embodiment, the distal portion 410 includes a first forceps head 412a and an opposing second forceps head 412b. At least one of the forceps heads 412a-b is movable relative to the axis of the forceps 400 such that a material, such as tissue, can be pressed or gripped between the forceps heads 412a-b and can also be released from between the forceps heads 412a-b. That is, as Figure 29 As shown, the tweezers 412a-b can be opened, creating a space between them to receive material. Figure 30 As shown, the forceps 412a-b can close together to grasp material. The movement of the forceps 412a-b can be actuated and controlled by the clinician 1 at the proximal end of the forceps 400 outside the patient.

[0133] Although in the depicted embodiment only the second forceps 412b is movable relative to the axis of the forceps 400, in some embodiments both the first forceps 412a and the opposing second forceps 412b are movable relative to the axis of the forceps 400. In some embodiments, three movable forceps are included in the forceps arrangement at the distal portion 410. In some embodiments, the forceps 400 (and / or any other instrument herein) includes one or more hinged portions through which the clinician 1 can controllably orient the distal portion 410.

[0134] In the depicted arrangement, endoscope 300 can be used to directly visualize at least the distal portion 410 of forceps 400. This feature is useful to clinician 1, as clinician 1 can use forceps 400 (and / or other instruments) for various purposes during the performance of surgery to treat hearing loss and other ear conditions as described herein. The ability to visualize at least the distal portion 410 of forceps 400 (and / or other instruments) during use within the middle ear 40 during surgery to treat hearing loss and other ear conditions as described herein helps clinician 1 to precisely position and operate the forceps 400 (and / or other instruments).

[0135] When instruments (e.g., endoscope 300, forceps 400, and any other instruments) are slidably positioned within the TM port device 200, the clinician 1 can manipulate the position and / or orientation of the instruments relative to the patient 10 in various ways. For example, the longitudinal insertion depth of the instruments can be manipulated by the clinician 1. In some embodiments, the instruments include one or more incremental depth markings (e.g., distance indicator scales). Such depth markings can help prevent over-insertion or damage to ear structures. Furthermore, the instruments can be rolled by the clinician 1 about the longitudinal axis of the instruments. Additionally, the pitch and / or yaw of the instruments can be adjusted / tilted by the clinician 1. By manipulating the position and / or orientation of the instruments as needed, and simultaneously using the direct visualization provided by the endoscope 300, the clinician 1 can perform surgery to treat hearing loss precisely and carefully.

[0136] Also refer to Figure 18 and 19 (This is a simulated image captured by endoscope 300). In some cases (but not all), patient 1 may have a pseudomembrane 51 covering all or part of the niche of the round window 52. In some cases, one or more other types of tissue may prevent access to the round window 52. When access to the round window 52 is partially or completely blocked, the clinician may use forceps 400 to open the entrance to the niche of the round window 52.

[0137] In the depicted example, tweezers 412a-b are open ( Figure 18And the forceps 400 are advanced toward the pseudomembrane 51. When the forceps 412a-b are near or in contact with the pseudomembrane 51, the clinician can actuate the forceps 412a-b to close and capture a portion of the pseudomembrane 51 between the forceps 412a-b. Then, while this portion of the pseudomembrane 51 is held between the forceps 412a-b, the clinician can manipulate the forceps 400 (e.g., pull the forceps 400 proximally) to open the entrance to the round window 52. Figure 19 In some cases, the pseudomembrane 51 will be torn open by such actions (without removing tissue). In some cases, a portion of the pseudomembrane 51 can be removed (completely separated from the surrounding tissue) by such actions.

[0138] The above description and corresponding figures explain how to use forceps 400 to achieve access to the circular window 52 (e.g., access to the circular window and the circular window membrane) when one or more obstructions are present. Furthermore, other tissue manipulator instruments and / or techniques disclosed herein can be used to achieve access to the circular window 52 when obstructions are present. These other tissue manipulator instruments and / or techniques also utilize direct visualization, provided by using endoscope 300. For example, Figure 20-23 This demonstrates how the suction device 500 can be used for this purpose. Additionally, Figure 24-27 The diagram illustrates how the expander device 600 or 700 can be used for this purpose.

[0139] refer to Figure 20-23 For reference above Figure 16 The and Figure 20 As shown again, at least the distal portion 310 of the endoscope 300 can be slidably advanced into the middle ear 40 via a first TM port device 200. Another instrument can be slidably advanced via a second TM port device 200. (See diagram below.) Figure 21-23 As shown, in this example, the suction device 500 is positioned as the second one in the TM port device 200. Thus, the distal portion 510 of the suction device 500 can be positioned within the middle ear 40.

[0140] Also refer to Figure 31 In some embodiments, the distal portion 510 of the aspiration device 500 may include a pointed member 512 and an aspiration port 514. The pointed member 512 may be used by the clinician 1 for various purposes, such as, but not limited to, puncturing, tearing, dissecting, and retracting tissue. The aspiration port 514 may be used by the clinician 1 to apply aspiration to perform various tasks, such as, but not limited to, removing fluid, removing particles, clearing deposits from tissue for dissecting, retracting, stretching / tearing, etc.

[0141] Figure 21 The distal portion 510 of the suction device 500 is shown being advanced within the middle ear 40 under direct visualization with the endoscope 300.

[0142] Figure 22 A simulated view from an endoscope 300 is shown on the distal portion 510 of a suction device 500 near the dummy membrane 51.

[0143] Figure 23 Another simulated view from an endoscope 300 is shown, which is on the tip member 512 and / or suction port 514 of a suction device 500, which is used by a clinician 1 to tear open the dummy membrane 51. With the dummy membrane 51 torn open, access to the round window 52 is obtained (e.g., access to the round window niche and access to the round window membrane).

[0144] refer to Figure 24-27 For reference above Figure 16 The and Figure 24 As shown again, at least the distal portion 310 of the endoscope 300 can be slidably advanced into the middle ear 40 via a first TM port device 200. Another instrument can be slidably advanced via a second TM port device 200. (See diagram below.) Figure 25-27 As shown, in this example, the expander device 600 is positioned through the second of the TM port devices 200. Thus, the distal portion 610 of the expander device 600 can be positioned within the middle ear 40.

[0145] Also refer to Figure 32 In some embodiments, the distal portion 610 of the dilator device 600 includes a first abduction member 612a and an opposing second abduction member 612b. The abduction members 612a-b can be actuated by a clinician 1 to open / close (e.g., Figure 32 (as shown) and closure (as shown) Figure 25 and 26 (as shown in the illustration). Therefore, the abduction members 612a-b can be used by the clinician 1 for various purposes, such as, but not limited to, separating, tearing, dissecting, stretching, retracting, etc. In some embodiments, as depicted, the distal tip of the abduction members 612a-b may be a blunt, damage-resistant tip.

[0146] Figure 25 The distal portion 610 of the dilator device 600 is shown being advanced within the middle ear 40 under direct visualization with an endoscope 300.

[0147] Figure 26 A simulated view from an endoscope 300 is shown on the distal portion 610 of an dilator device 600 near a pseudo-diaphragm 51.

[0148] Figure 27Another simulated view of the endoscope 300 from the abduction members 612a-b of the dilator device 600 is shown, which is being used by the clinician 1 to expand and tear open the pseudomembrane 51. With the pseudomembrane 51 torn open, access to the round window 52 is obtained (e.g., access to the round window niche and access to the round window membrane).

[0149] refer to Figure 33 Another exemplary embodiment of the dilator device 700 can be used to dilate and tear the pseudomembrane 51 in a manner very similar to that used in the dilator device 600 described above. However, compared to the blunt, injury-resistant tips of the abduction members 612a-b, the abduction members 712a and 712b of the dilator device 700 include pointed members 714a and 714b, respectively. As shown, the pointed members 714a-714b can extend laterally at an angle from the axis of the dilator device 700, and the pointed members 714a-714b can be used to puncture tissue, such as the pseudomembrane 51. Thereafter, the abduction members 712a and 712b can be advanced distally and subsequently opened by a clinician 1 (e.g., Figure 33 (as shown) to expand the false membrane 51 so that access to the round window 52 (e.g., access to the round window niche and access to the round window membrane).

[0150] While the dilator device 700 includes abduction members 712a and 712b, wherein pointed members 714a and 714b extend laterally at an angle, in some embodiments, side-biting scissors may be used additionally or alternatively for the procedures described herein. Such side-biting scissors may include two blades that are pivotable relative to each other to cut tissue between them. In some embodiments, a pair of blades (or their end portions) may extend laterally from the axis of the scissors at an angle (e.g., 30° to 60° or 20° to 80°, but not limited thereto).

[0151] While many different instruments and techniques for removing obstructions to create access to the niche of the round window 52 have been described above, in some patients, no such obstruction needs to be removed. Due to these patient differences, the clinician 1 may first advance the endoscope 300 into the middle ear 40 via one of the TM port devices 200 and then visually examine the middle ear 40 and cochlea 50 (including the area of ​​the round window 52) to determine if any obstruction needs to be removed to obtain adequate access to the niche of the round window 52. If an obstruction exists (based on visual examination using the endoscope 300), one or more of the instruments and techniques for removing the obstruction to create access to the niche of the round window 52 can be used. If no obstruction exists (based on visual examination using the endoscope 300), then it is not necessary to perform the instruments and techniques for removing the obstruction to create access to the niche of the round window 52. Therefore, instruments and techniques for removing obstructions to create access to the cochlea 50 via the round window 52 can be used as needed. As a reference point, some estimates suggest that patients with a pseudomembrane 51 covering the round window 52 account for approximately 40% of all patients.

[0152] refer to Figure 34 Once the opening of the niche to the round window 52 has been verified and the endoscope 300 is slidably positioned through the first of the TM port devices 200, the syringe device 800 can then be slidably advanced by the clinician 1 through the second of the TM port devices 200. The distal portion 810 of the syringe device 800 can thus be selectively positioned within the middle ear 40 while being directly visualized using the endoscope 300. As described below, the syringe device 800 will be used to deliver the therapeutic agent 100 to a location near the round window 52 (e.g., to a round window niche adjacent to the round window membrane of the cochlea 50, where the active ingredient of the therapeutic agent 100 can be passively moved by diffusion across the membrane of the round window 52) or to other target locations on or within the cochlea 50 of the patient 10.

[0153] Also refer to Figure 41 An exemplary syringe device 800 is shown in more detail herein. In the depicted embodiment, the syringe device 800 includes a sheath 802 and an injection tube 820. The injection tube 820 is slidable within a lumen defined by the sheath 802. That is, as depicted herein, the injection tube 820 can be selectively extended distally by a clinician 1 from the distal end of the sheath 802. Furthermore, the injection tube 820 can be selectively retracted proximally by the clinician 1 into the sheath 802 such that the injection tube 820 does not extend beyond the distal end of the sheath 802. When the injection tube 820 is extended (as shown), the exposed portion of the injection tube 820 constitutes a distal portion 810 of the syringe device 800. The distal portion 810 terminates at a distal tip 812, which defines a port through which a therapeutic agent or drug is ejected.

[0154] The portion of the syringe tube 820 constituting the distal portion 810 of the syringe device 800 can have various shape and form factors. For example, in the depicted example, the exposed syringe tube 820 includes a linear portion 822, a first curved portion 824, and a second curved portion 826. However, when the syringe tube 820 is confined within the sheath 802, the curved portions 824 and 826 become linear. Alternatively, if the lumen of the syringe tube 820 is not linear, then the curved portions 824 and 826 take on the shape of that lumen.

[0155] It can be said that the curved portions 824 and 826 have shape memory. That is, when the clinician 1 extends the curved portions 824 and 826 from the constraints of the sheath 802, the curved portions 824 and 826 will return to the curved shape shown.

[0156] In a particular embodiment, the combination of the first curved portion 824 and the second curved portion 826 defines an "S-shape" for the distal portion 810 of the syringe device 800. This S-shape is formed because the first curved portion 824 bends in the opposite direction to the curve of the second curved portion 826. In other words, the center point of the radius of curvature of the first curved portion 824 is on the opposite side of the syringe tube 820, compared to the center point of the radius of curvature of the second curved portion 826. It should be understood that this shape of the syringe tube 820 having the linear portion 822, the first curved portion 824, and the second curved portion 826 is merely one example of the types of shapes the syringe tube 820 can have. Other shapes are also contemplated (e.g., but not limited to, those described below). Figures 38-40 (The shape shown) is within the scope of this disclosure.

[0157] It is conceivable that when the clinician 1 begins to extend the syringe 820 distally from the distal end of the sheath 802, the second bend 826 will appear first. Therefore, the distal portion 810 will initially have a single bend (as shown by the second bend 826). If the clinician 1 continues to extend the syringe 820 distally from the distal end of the sheath 802, then eventually the first bend 824 will begin to appear. When the first bend 824 appears, it is conceivable that the entire distal portion 810 will deflect correspondingly in the opposite direction to the second bend 826.

[0158] As the injection tube 820 extends distally from the sheath 802 to various degrees, the distal tip 812 will move into each position due to the shape memory of the first curved portion 824 and the second curved portion 826. Therefore, the distal tip 812 can be controllably positioned by the clinician 1 by controlling the degree to which the injection tube 820 extends distally from the sheath 802 and by using the axial rotation of the instrument 800. In other words, the clinician 1 can steer the distal portion 810, and particularly the distal tip 812, by controlling the degree to which the injection tube 820 extends distally from the sheath 802. This function can be used by the clinician 1 to accurately position the distal tip 812 within the round window 52 in preparation for injecting a therapeutic agent through the round window 52.

[0159] Although the distal portion 810 includes a first curved portion 824 and a second curved portion 826 that are in the same plane but bend in opposite directions, in some embodiments, the distal portion 810 may include two or more curved portions that are in different planes.

[0160] In some embodiments, the shape of the distal portion 810 can be selectively controlled by the clinician 1 using a control member located within a lumen defined within the wall of the injection tube 820. For example, Figure 42 Some exemplary cross sections of various pipe configurations are shown (e.g., along) Figure 41 (Extended by dashed lines 42-42 in the diagram), the injection tube 820 can be made from these various tube configurations. For example, it can be seen that tube 820a includes a first pair of lumens 821a and 821b opposite each other at 180°. In some embodiments, such lumens 821a-b may accommodate, for example, a control line anchored near the distal tip 812. Thus, when the clinician 1 pulls one of the lines proximally and relaxes the tension on the other opposing line, the distal portion 810 will deflect in the direction of the taut line. In this way, the clinician 1 can turn the distal portion 810 as needed.

[0161] Furthermore, the exemplary tube 820a also includes a second pair of lumens 823a and 823b. These lumens 823a-b define a plane perpendicular to the plane defined by the first pair of lumens 821a-b. Again, the second pair of lumens 823a-b may accommodate, for example, a control line anchored near the distal tip 812. Thus, when the clinician 1 pulls one of the lines proximally and relaxes the tension on the other opposing line, the distal portion 810 will deflect in the direction of the taut line.

[0162] If all four of the lumens 821a-b and 823a-b accommodate such control leads, then it is conceivable that the clinician 1 can control the orientation or steering to allow the distal portion 810 to extend in any direction and have any orientation as needed. Furthermore, when the distal portion 810 has a shape memory including one or more bends (e.g., as...), Figure 41 This is true (as depicted) or in any case where the distal portion 810 is naturally linear.

[0163] While exemplary tube 820a has a specific arrangement of lumens 821a-b and 823a-b, other exemplary tubes 820b and 820c have other arrangements of lumens. Therefore, tubes 820b and 820c, or tubes with any other arrangement of lumens, may also be used in accordance with the concepts described in the exemplary context of tube 820a.

[0164] In some embodiments, the lumen within the wall of the injection tube (e.g., lumens 821a-b and 823a-b of injection tube 820a) may accommodate control members serving as reinforcing elements. Such reinforcing elements can also be used to controllably deflect or steer the distal portion 810. For example, in some embodiments, the injection tube 820 naturally has one or more bends (e.g., a first bend portion 824 and a second bend portion 826). When a reinforcing element (e.g., a strong, bend-resistant linear shaft) moves distally through the lumen within the wall of the injection tube 820 and into the region of the bend, the bend will tend to straighten. Conversely, when these reinforcing elements are pulled proximally from the region of the bend, they will revert to a bend. By using reinforcing elements in the wall of the injection tube 820 in this manner, the clinician 1 can control the orientation or steer to allow the distal portion 810 to extend in any direction and have any orientation as needed. Conversely, in some embodiments, the reinforcing element may have a pre-shaped bend (e.g., a biased laser-cut wire or hyaluronic acid tube, a shape memory element or wire, or a hyaluronic acid tube made of a material (e.g., nitinol), while the injection tube 820 is generally straight. Such a reinforcing member can be pushed relative to a relatively inflexible distal end of the entry axis, such that the bend of the reinforcing member applies a bend towards the distal tip of the injection tube. It is conceivable that reinforcing elements with different degrees of pre-defined bend can be switched out to adjust the curvature, while allowing the injection tube 820 to remain in place and thereby limiting potential interference with the TM30. In another embodiment, the reinforcing member may be a shape memory element (e.g., nitinol) that will exhibit its bend upon exposure to an elevated temperature (e.g., the temperature inside the patient). In other embodiments, the elevated temperature may be greater than the patient's internal temperature. In this case, the elevated temperature can be achieved by applying a voltage to the nitinol element, by exposing it to heat generated by a light source, or by another technique for heating the nitinol element.

[0165] Figures 38-40 Another exemplary syringe device 900 is shown. In the depicted embodiment, the syringe device 900 includes a sheath 902 and an injection tube 920. The injection tube 920 is slidable within a lumen defined by the sheath 902. That is, as Figure 39 and 40 As shown, the injection tube 920 can be selectively extended distally from the distal end of the sheath 902 by the clinician 1. Furthermore, as... Figure 38 As shown, the injection tube 920 can be selectively retracted proximally into the sheath 902 by the clinician 1, so that the injection tube 920 does not extend beyond the distal end of the sheath 902. When the injection tube 890 extends (e.g. Figure 39 and 40 As shown, the exposed portion of the injection tube 920 constitutes the distal portion 910 of the syringe device 900. The distal portion 910 terminates at an angled distal tip 912, which defines a port through which a therapeutic agent or drug is ejected.

[0166] The syringe device 900 may have any of the features described above with reference to the syringe device 800 (including control components), except that the syringe tube 920 of the syringe device 900 has only a single naturally curved portion. However, the extension direction and orientation of the distal portion 910 (and the distal tip 912) can be essentially controlled by the clinician 1 by controlling factors such as the length of the distal portion 910 and the roll, pitch, and yaw of the syringe device 900 relative to the patient 1.

[0167] Now for reference Figure 35 Under direct visualization with endoscope 300 (where the distal portion 310 is visible), clinician 1 can controllably manipulate and orient the distal portion 810 of injection tube 820 such that the distal tip 812 is within or adjacent to the niche of round window 52. For this purpose, clinician 1 can use any of the techniques described above for deflection, steering, articulation, extension, and other orienting of the distal portion 810.

[0168] Also refer to Figure 36 Once the distal tip 812 is correctly positioned relative to the round window 52 (which can be confirmed by direct visualization using endoscope 300 by clinician 1), clinician 1 can then deliver the required amount of therapeutic agent 100 into the round window niche adjacent to the round window membrane of the cochlea 50. This delivery can also be performed under direct visualization using endoscope 300. That is, clinician 1 can use endoscope 300 to confirm that the therapeutic agent 100 has been delivered in the required amount and is in the desired position. Furthermore, clinician 1 can use endoscope 300 to monitor over a period of time whether the therapeutic agent 100 remains in the desired position rather than migrating away from it.

[0169] The delivered therapeutic agent 100 will tend to remain in the desired position because the therapeutic agent 100 is delivered as a gel or will turn into a gel in place.

[0170] refer to Figure 37 In some embodiments, the therapeutic agent 100 may solidify in situ or partially solidify (to become a gel) immediately after delivery into the cochlea 50. In some such embodiments, light energy (e.g., UV light) for accelerating the solidification of the therapeutic agent 100 may be applied by an endoscope 300 as depicted or by another instrument. In other embodiments, the therapeutic agent 100 is a thermoresponsive hydrogel that is liquid at room temperature and forms a gel at body temperature.

[0171] refer to Figure 43 In some embodiments, when the two liquid components are mixed together, for example via an exemplary dual-injector 1000, the therapeutic formulation 100 begins to transform into a gel substance. The dual-injector 1000 mixes the two liquid components during injection such that the two liquid components are mixed just before delivery. The gelation reaction time between the two liquid components causes the homogeneous mixture of the two liquid components to rapidly transform into a gel consistency, which is consistent with the design of the dual-injector 1000.

[0172] The dual syringe 1000 includes a first barrel 1010, a second barrel 1020, dual plungers 1030, a Y connector 1040, and a static mixer 1050. The outlet of the static mixer 1050 is releasably connected to a syringe device, such as syringe device 800.

[0173] The first cylinder 1010 and the second cylinder 1020 respectively contain a first liquid component and a second liquid component, and the first liquid component and the second liquid component are kept separate from each other while in the first cylinder 1010 and the second cylinder 1020. The dual plunger 1030 includes two plungers (one in the first cylinder 1010 and one in the second cylinder 1020), the two plungers being coupled together such that the displacement of the two plungers generated by the clinician 1 is synchronized during injection. The Y-connector 1040 receives the first liquid component and the second liquid component output from the first cylinder 1010 and the second cylinder 1020, and guides the first liquid component and the second liquid component to flow and contact each other at the outlet of the Y-connector 1040. The static mixer 1050 receives the first liquid component and the second liquid component from the Y-connector 1040, and causes the first liquid component and the second liquid component to mix together to produce a homogeneous mixture of the first liquid component and the second liquid component. A homogeneous mixture of the first and second liquid components output from the static mixer 1050 can be fed into a syringe device 800, from which the homogeneous mixture of the first and second liquid components can be delivered to the cochlea 50 of a nearby patient 10.

[0174] In another embodiment, a single syringe can be used to deliver the therapeutic formulation 100. In this case, the gel time of the formulation components of the therapeutic formulation 100 is tuned such that the formulation components can be mixed at the patient's bedside and immediately (before the cross-linking reaction of the formulation components or the majority of the cross-linking reaction occurs) delivered into the cochlea 50 using a standard single syringe attached to a syringe device. Furthermore, in some embodiments, photocrosslinking (e.g., Figure 37 Therefore, in some embodiments, immediately after the mixed formulation components are delivered into the niche of the round window 52, ​​light is applied toward the round window 52 into the middle ear 40 to initiate and / or accelerate cross-linking, and to produce the gel consistency of the therapeutic formulation 100. In some embodiments, the gel consistency is produced upon exposure to heat generated by the patient's own body or by another device.

[0175] The gel consistency of the therapeutic formulation 100 causes it to remain adjacent to the round window membrane of the cochlea 50 and promotes the short-term or sustained release of the active ingredient of the therapeutic formulation 100. Sustained release may encompass the release of an effective amount of the active ingredient of the therapeutic formulation 100 over a prolonged period. Sustained release may include first-order release of the active ingredient, zero-order release of the active ingredient, or other release kinetics, such as an intermediate stage between zero-order and first-order, or a combination thereof. Sustained release may include controlling the release of the therapeutic formulation 100 by passive molecular diffusion driven by a concentration gradient across the porous structure.

[0176] The composition of therapeutic formulation 100 can be a mixture. It can be a solution, suspension, emulsion, liquid, powder, paste, aqueous, non-aqueous, or any combination of such components. A fluid is any composition that can flow. Therefore, fluid encompasses compositions in the form of semi-solids, pastes, solutions, aqueous mixtures, gels, lotions, creams, and other such compositions.

[0177] In some embodiments, the ear composition (e.g., a sustained-release ear composition) may be delivered to a subject from or by means of the therapeutic device described herein. In some embodiments, the sustained-release ear composition may include a polymer composition capable of forming a gel. For example, the polymer composition may include a functional polymer, wherein the functional polymer includes a first functional group and a crosslinking agent, wherein the crosslinking agent includes a second functional group and water, wherein a crosslinking reaction may occur between the first and second functional groups to form a gel. In some embodiments, the functional polymer may be present in an amount of about 5% to about 15% by weight of the polymer composition. In some embodiments, the crosslinking agent may be present in an amount of about 0.2% to about 0.6% by weight of the polymer composition.

[0178] It should be understood that the first functional group (e.g., on the functional polymer) and the second functional group (e.g., on the crosslinking agent) should enable a crosslinking reaction. Therefore, the selection of the functional polymer can be based on the selection of the crosslinking agent, and vice versa. In some embodiments, the first functional group may be an N-hydroxysuccinimide (NHS) group, and the second functional group may be an amine (e.g., a primary amine), or vice versa. In some cases, each of the functional polymers contains only electrophilic or nucleophilic functional groups, and the crosslinking agent contains only nucleophilic or electrophilic functional groups.

[0179] In some embodiments, the functional polymer is a multi-arm (e.g., 3-arm, 4-arm, 6-arm, or 8-arm) polyethylene glycol (PEG) comprising two or more succinimidyl ester (e.g., succinimidyl succinate or succinimidyl glutarate) or sulfonyl-succinimidyl ester functional groups, and the crosslinking agent contains multiple amine (e.g., primary amine) functional groups. In some embodiments, the multi-arm PEG may have two or more arms terminated in the succinimidyl ester functional groups. In some embodiments, one or more monomers of the multi-arm PEG may include succinimidyl ester functional groups. In some embodiments, the crosslinking agent may be polylysine (e.g., ε-polylysine) (e.g., trilysine, tetralysine, or pentyllysine). For example, in some embodiments, the functional polymer may be pentaethylene glycol poly(ethylene glycol) ether tetrasuccinimidyl glutarate, and the crosslinking agent may be trilysine.

[0180] In some embodiments, the functional polymer is a multi-arm (e.g., 3-arm, 4-arm, 6-arm, or 8-arm) polyethylene glycol containing two or more amine (e.g., primary amine) functional groups, and the crosslinking agent comprises a plurality of succinimide esters (e.g., succinamide succinate or succinamide glutarate) or sulfosuccinimide ester functional groups. In some embodiments, the multi-arm PEG may have two or more arms terminated in an amine (e.g., primary amine) functional group. In some embodiments, one or more monomers of the multi-arm PEG may comprise amine (e.g., primary amine) functional groups. In some embodiments, the crosslinking agent may be glutarimide glutarate, succinamide diimide succinate, bis(sulfosuccinamide) succinate, or succinamide diimide succinate.

[0181] In some embodiments, the sustained-release otomedicine composition may include an active agent (e.g., a therapeutic agent, a preventative agent, a diagnostic agent, or a visualization agent, or a combination thereof). The active agent may include, for example, proteins (e.g., enzymes, growth factors, antibodies, or antigen-binding fragments thereof), carbohydrates (e.g., glycosaminoglycans), nucleic acids (e.g., antisense oligonucleotides, aptamers, microRNAs, short interfering RNAs, or ribonucleases), small molecules, or combinations thereof. In some embodiments, the small molecule may include antibiotics, antitumor agents (e.g., doxorubicin), local anesthetics, steroids, hormones, apoptosis inhibitors (e.g., inhibitors of Apaf-1; see, for example, U.S. Patent No. 9,040,701, which is incorporated herein by reference in its entirety), angiogenic agents, anti-angiogenic agents (e.g., VEGF inhibitors), neurotransmitters, psychoactive drugs, anti-inflammatory agents, and combinations thereof.

[0182] In some embodiments, the active agent may include an anti-angiogenic agent. In some embodiments, the anti-angiogenic agent may be a VEGF inhibitor. In some cases, the VEGF inhibitor may be an antibody or its antigen-binding fragment, a decoy receptor, a VEGFR kinase inhibitor, a VEGFR allosteric modulator, or a combination thereof. In some cases, the VEGF inhibitor may be an antibody or its antigen-binding fragment. For example, in some embodiments, the VEGF inhibitor may be arazumab or bevacizumab. Irucumab (IMC-18F1), Ramolizumab (LY3009806, IMC-1121B), or lanizumab In some embodiments, the VEGF inhibitor may be a decoy receptor (e.g., aflibercept). In some embodiments, the VEGF inhibitor may be a VEGFR kinase inhibitor, such as agrafenib, ateratinib, apatinib, axitinib, cabozantinib, sildenafil, lapatinib, lenbatinib, motizab, nitidanib, parzopanib, peragatanib, rebatinib, regorafenib, cesmasanib, sorafenib, sunitinib, tolanib, tevozaniib, or vandetanib. Other examples of VEGF inhibitors may be known in the art. In some embodiments, the VEGFR inhibitor may be an allosteric regulator of VEGFR (e.g., cycloaspergillus B).

[0183] In some cases, sustained-release otological compositions can be used to treat ear diseases or conditions such as Meniere's disease (MD), autoimmune inner ear disease (AIED), sudden sensorineural hearing loss (SSNHL), noise-induced hearing loss (NIHL), age-related hearing loss, sensorineural hearing loss associated with diabetes, tinnitus, damaged cilia due to autoimmune diseases, damaged cilia due to infection, damaged cilia due to excessive fluid or stress, hearing loss due to chemotherapy, or a combination thereof.

[0184] Therapeutic agents that can be delivered from or by means of the therapeutic devices described herein may include, but are not limited to, antioxidants, anti-inflammatory agents, steroids, antimicrobial agents, NMDA receptor antagonists, anisotropic agents, anti-apoptotic agents, neurotrophic proteins, neuroprotective agents, neuroprotective proteins such as CNTF, BDNF, PEDF, NGF, etc., cannabinoids, monoclonal antibodies, other proteins, gene therapy, iRNA, tyrosine kinase inhibitors (TKIs), dileucine zipperase (DLK) inhibitors, and protein therapies similar to anti-VEGF.

[0185] For example, therapeutic agents may include, but are not limited to, antimicrobial agents, such as antibiotics, including tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, bacitracin, cephalexin, oxytetracycline, chloramphenicol, kanamycin, rifampin, ciprofloxacin, tobramycin, gentamicin, erythromycin, and penicillin; antifungal agents, such as amphotericin B and miconazole; antibacterial agents, such as sulfonamides, sulfadiazine, sulfaacetamide, sulfamethoxazole, sulfamethoxazole, furacilin, and sodium propionate; antiviral drugs, such as iodoureidin, trifluorothymidine, acyclovir, ganciclovir, and interferon; and antiallergic agents, such as sodium cromoglycate, acetaminophen, and acetaminophen. Tazoline, methoxypyrimidine, chlorpheniramine, pyramine, cetirizine, and phenpyridine; anti-inflammatory drugs, such as hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone acetonide, metronidazole, prednisolone, prednisolone 21-phosphate, prednisolone acetate, flumethasone, betamethasone, and triamcinolone; nonsteroidal anti-inflammatory drugs, such as salicylates, indomethacin, ibuprofen, diclofenac, flurbiprofen, and piroxicam; decongestants, such as phenylephrine, naphazoline, and tetrahydrozoline; miotics and anticholinesterases, such as pilocarpine, salicylates, acetylcholine chloride, and toxic substances. Physostigmine, serine, carbacholine, diisopropyl fluorophosphate, phosphine iodide, and desmodium bromide; mydriatics such as atropine sulfate, cyclopentolpine, homatropine, scopolamine, toxicamine, eucatropine, and amphetamine; sympathomimetic drugs such as adrenaline; antitumor drugs such as carmustine, cisplatin, and fluorouracil; immunomodulatory drugs such as vaccines and immunostimulants; hormones such as estrogens, estradiol, progesterone, insulin, calcitonin, parathyroid hormone, peptides, and vasopressin-hypothalamic releasing factor; β-adrenergic blockers such as timolol maleate, levobrolol hydrochloride, and succinate. Betalol; growth factors, such as epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, transforming growth factor β, growth hormone, and fibronectin; carbonic anhydrase inhibitors such as dichloroaniline, acetazolamide, and metronidazole, as well as other drugs such as prostaglandins, anti-prostaglandins, and prostaglandin precursors; antioxidants, NMDA receptor antagonists, nootropics, anti-apoptotic agents, neurotrophic factors, neuroprotective agents, tyrosine kinase inhibitors (TKIs), bisleucine zipper kinase (DLK) inhibitors, cannabinoids, monoclonal antibodies, antibody fragments, other proteins, and gene therapies. Other therapeutic agents known to those skilled in the art that can be controlled and sustainedly released into the ear in the manner described herein are also suitable for use in embodiments of the device described herein.

[0186] Therapeutic agents may include, but are not limited to: sodium thiosulfate for the prevention of cisplatin-induced hearing loss; an NMDA receptor antagonist (AM-101; Auris Medical) for the treatment of tinnitus; a synthetic peptide-containing D-JNKI-1 (the D-stereoisomer of c-Jun N-terminal kinase inhibitor 1; Auris Medical) for the protection against acute inner ear hearing loss; dexamethasone for the treatment of Meniere's disease; D-methionine (Southern Illinois University) for the prevention of noise-induced hearing loss; LY411575 (a selective Y secretase inhibitor that blocks Notch activation); and NT-3 neurotrophic factor.

[0187] The therapeutic agents may include, but are not limited to, local anesthetics for delivery into the ear canal, including benzocaine, antipyridine, butylcaine, dibutylcaine, lidocaine, procaine, oxycaine, pramocin, paracaine, methylcaine, and tetracaine.

[0188] Various pharmaceutically acceptable carriers used for the therapeutic agents described herein may include, for example: solids, such as starch, gelatin, sugar, natural gums such as gum arabic, sodium alginate, and carboxymethyl cellulose; polymers, such as silicone rubber; liquids, such as sterile water, saline, glucose, aqueous glucose solution, or saline; condensation products of castor oil and ethylene oxide, liquid triglycerides of low molecular weight fatty acids; lower alkanols; oils, such as corn oil, peanut oil, sesame oil, castor oil, etc., having emulsifiers such as monoglycerides or diglycerides of fatty acids, or phospholipids such as lecithin, polysorbate 80, etc.; ethylene glycol and polyalkylene glycols, including P407, and other combinations of polyethylene glycol and polypropylene glycol; aqueous media containing suspending agents, such as sodium carboxymethyl cellulose, hyaluronic acid, sodium hyaluronate, sodium alginate, polyvinylpyrrolidone, and similar compounds, either alone or with suitable disintegrants, such as lecithin, cyclodextrin, polyoxyethylene stearate, etc. The carrier may also contain adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers or other related materials.

[0189] Therapeutic agents mentioned with trade names encompass one or more of the following: formulations of commercially available therapeutic agents under a trade name, the active ingredient of a commercially available formulation, a generic name of the active ingredient, or a molecule containing the active ingredient. As used herein, a therapeutic agent or therapeutic agent is a medicine that improves the symptoms of a disease or condition. Therapeutic agents, therapeutic compounds, treatment regimens, or chemotherapy include conventional medicines and drug therapies, including vaccines known to those skilled in the art and described elsewhere herein. Therapeutic agents include, but are not limited to, moieties that can be controlled and released into the body.

[0190] refer to Figure 44An exemplary method 1100 for treating a patient's hearing loss is depicted in the illustrated flowchart. Method 1100 can be performed by one or more clinicians and results in the injection of one or more therapeutic agents into the patient's cochlea. Method 1100 can be consistent with, but is not limited to, the techniques for treating hearing loss described above.

[0191] Method 1100 is a minimally invasive procedure. In some cases, method 1100 can be performed using local anesthetics without the need for general anesthesia. In specific circumstances, general anesthesia can be used to perform method 1100.

[0192] In operation 1110, one or more stabilizers are installed in the patient's tympanic membrane (TM). In some embodiments, the stabilizer may be the TM port device 200 described above. For example, this TM port device 200 may be installed using the TM port inserter 220 in the manner described above. In some cases, a single stabilizer is installed in the TM. In certain cases, a total of two stabilizers are installed in the TM. In other cases, three or more stabilizers are installed in the TM. As described above, the stabilizer may serve as a retainer, a decompression member to prevent TM tearing, a middle ear access port, an instrument insertion channel, a working channel, etc.

[0193] In operation 1120, the endoscope is inserted through a stabilizer (which is implanted in the TM). As the endoscope is inserted through the stabilizer (e.g., through the lumen defined by the stabilizer), the distal portion of the endoscope is positioned within the middle ear. The endoscope may include a light source and image capture capabilities as described above with reference to endoscope 300. Therefore, images of the middle and inner ear can be obtained using the endoscope and visualized by a clinician outside the patient via the instrument itself, an external display, an external head-mounted device, a 3D display, or the like. The clinician can manipulate the orientation and insertion depth of the endoscope to obtain images of various structures visible from within the middle ear. In some embodiments, the endoscope may be steerable or articulated to assist the clinician in such manipulations.

[0194] In procedure 1130, the clinician can use an endoscope to visualize potential obstructions to the round window of the cochlea. From the images obtained using the endoscope, the clinician can then determine if there are any obstructions that need to be relieved in order to achieve adequate access to the round window of the cochlea. For example, some patients may have a pseudomembrane covering the round window. In some cases, other tissues or obstructions may be present.

[0195] If the clinician determines that there are no obstructions requiring relief at the round window niche or other target sites in the cochlea, then method 1100 proceeds to operation 1170. However, if the clinician determines that there are obstructions requiring relief at the round window niche, then method 1100 proceeds to operation 1140.

[0196] At optional operation 1140, the clinician inserts the tissue-modifying device into the second stabilizer (which is simultaneously implanted in the TM). Simultaneously, the endoscope remains inserted through the first stabilizer. Therefore, both the distal portions of the tissue-modifying device and the endoscope are within the middle ear (e.g., see...). Figure 17-19 21-23 and 25-27). Various types of tissue modification devices can be selectively used by clinicians (e.g., forceps 400, aspiration device 500, dilator device 600 and 700, etc.).

[0197] At optional operation 1150, the clinician uses an inserted tissue-modifying device to open the entrance to the round window niche into the cochlea. For example, if a pseudomembrane covers the round window niche, the clinician can tear and / or remove a portion of such a pseudomembrane. Other types of obstruction can be relieved by the clinician in an appropriate manner. These actions can be performed with direct visualization using an endoscope.

[0198] At optional operation 1160, the clinician removes the tissue modification device from the middle ear and from the stabilizer through which the tissue modification device extends.

[0199] At operation 1170, the clinician inserts a therapeutic injection device through a stabilizer (which is simultaneously implanted in the TM). Simultaneously, the endoscope remains inserted through the first stabilizer. In some embodiments, the endoscope can be used to "track" the therapeutic injection device along the ear canal and provide visualization of the insertion of the therapeutic injection device through the stabilizer. Therefore, in some embodiments, the therapeutic injection device can be advanced before the endoscope.

[0200] Therefore, the distal portions of both the injection instruments and the endoscope are located within the middle ear (e.g., reference...). Figures 34-36 Various types of therapeutic agent delivery devices may be selectively used by clinicians (e.g., therapeutic agent injection devices 800 and 900, etc.). Any features of the aforementioned injection devices 800 and 900 may be included in the injection device in any combination. In this case, the source of the therapeutic agent may be coupled to the therapeutic agent injection device, or the source may be coupled to the therapeutic agent injection device later (e.g., just before its injection).

[0201] At operation 1180, the clinician advances the distal port of the therapeutic injection device into the niche of the round window or a niche adjacent to the round window. To this end, as described above, the clinician can controllably manipulate, steer, deflect, translate, roll, yaw, and control the insertion depth of the syringe device to position the distal port of the therapeutic injection into the niche of the round window or a niche adjacent to the round window. These actions can be performed with direct visualization using an endoscope.

[0202] At procedure 1190, the clinician uses an injection device to deliver the therapeutic agent into the round window niche adjacent to the round window membrane, or to other target sites on or near the cochlea. These actions can be performed with direct visualization using an endoscope.

[0203] In some cases, the homogeneous mixing of the two components of the therapeutic agent is performed as part of the injection procedure (e.g., as referenced). Figure 43 (As described above). In certain cases, the therapeutic agent is mixed just before use and the mixture is delivered from a single reservoir (e.g., a syringe). In some cases, light energy (e.g., UV light) to accelerate the curing of the therapeutic agent can be applied in situ via an endoscope or another instrument (e.g., as referenced above). Figure 37 The above).

[0204] In optional operation 1200, the clinician can use an endoscope to visually verify that the therapeutic agent is retained as needed in the round window niche of the cochlea. As described above, the therapeutic agent is a gel-like substance or quickly becomes a gel-like substance, such that the therapeutic agent is intended to be retained as a block in the round window niche adjacent to the round window membrane of the cochlea. This facilitates the controlled release of the active ingredient of the therapeutic agent over a period of time. Therefore, in this operation 1200, the clinician can take steps to confirm that the therapeutic agent is retained as a block in the cochlea as needed.

[0205] At operation 1210, the clinician can remove the instrument from the patient. The instrument to be removed may include an endoscope, an injection device, and one or more stabilizers (e.g., a TM port device as described above). To facilitate stabilizer removal, in some embodiments, the stabilizer has a small physical feature, such as a tab, at its proximal end that allows for easy grasping and removal using forceps. Alternatively, a removal tool may be used to penetrate the lumen of the stabilizer and then “abduct” upon actuation. The removal tool can then be used to pull the stabilizer out of the TM.

[0206] Figure 45 An exemplary otological instrument 1200 is shown engaging with an optional movable sleeve device 1300. The sleeve device 1300 includes a main tube 1310 and one or more secondary tubes defining one or more auxiliary working channels 1320 that can receive additional instruments, as further described below.

[0207] The sleeve device 1300 is removably coupled to the shaft 1220 of the instrument 1200. The sleeve device 1300 may have various configurations (described further below) and is slidably engaged with and removed from the shaft 1220 of the instrument 1200. The sleeve device 1300 may be made of a metal (e.g., stainless steel, titanium, aluminum, etc.) or a plastic material. In some embodiments, the sleeve device 1300 is transparent.

[0208] In the depicted embodiment, the otological instrument 1200 is an endoscope 1210 with a handle. However, in addition to the depicted endoscope 1200, the sleeve device 1300 can be used with a variety of other types of otological instruments as described herein. In one exemplary arrangement using the sleeve device 1300, the instrument 1200 is an endoscope and a syringe device extends through an auxiliary working channel defined by the sleeve device 1300. In some such embodiments, the distal tip portion of the syringe device may have a natural curve, such that the distal tip portion of the syringe device can be controllably guided to a position that is non-linear with respect to the longitudinal axis of the auxiliary working channel.

[0209] The sleeve device 1300 may have various lengths relative to the length of the shaft 1220. In some embodiments, the sleeve device 1300 will extend through the TM port device during use. In some embodiments, the distal end of the sleeve device 1300 will be located at the proximal end of the TM port device, such that the sleeve device 1300 will not extend through the TM port device during use.

[0210] In some embodiments, the central longitudinal axes of the main tube 1310 and the one or more secondary tubes defining one or more auxiliary working channels 1320 extend parallel to each other (e.g., as shown in the figure). Figure 45(As shown). Alternatively, in some embodiments, the central longitudinal axes of the main pipe 1310 and the one or more secondary pipes defining one or more auxiliary working channels 1320 extend in a non-parallel relationship (e.g., a non-zero angle is defined between the main pipe 1310 and the one or more secondary pipes defining one or more auxiliary working channels 1320). For example, in some embodiments, the angle defined between the main pipe 1310 and the one or more secondary pipes defining one or more auxiliary working channels 1320 is between 0° and 5°, or between 0° and 10°, or between 0° and 20°, or between 0° and 30°, or between 5° and 10°, or between 5° and 15°, or between 10° and 15°, or between 10° and 20°, or between 10° and 30°, and is not limited thereto, wherein the one or more secondary pipes... In some embodiments, the sleeve device 1300 may be adjustable, allowing a clinician to select / customize the angle defined between the main tube 1310 and the central longitudinal axis of one or more secondary tubes, wherein the one or more secondary tubes define one or more auxiliary working channels 1320. In some embodiments, this may be advantageous because it can reduce the effective diameter of the instrument passing through the TM by aligning the instrument through the auxiliary working channel with the instrument or endoscope that serves as the central longitudinal axis and effectively eliminating any wall thickness between the two channels.

[0211] Figures 46-48 This is a non-limiting exemplary cross-sectional view of the sleeve device 1300 taken at section AA. Figure 46 A cross-sectional view of the sleeve device 1300a is depicted. Figure 47 A cross-sectional view of the sleeve device 1300b is depicted. Figure 48 A cross-sectional view of the sleeve device 1300c is depicted.

[0212] Each of the sleeve devices 1300a to 1300c includes a main tube 1310 defining an inner cavity 1312. The inner cavity 1312 is configured to slidably receive the shaft 1220 of the instrument 1200 (e.g., Figure 45 (As shown in the diagram). When the sleeve devices 1300a to 1300c are slidably coupled to the shaft 1220, the sleeve devices 1300a to 1300c can be adjusted and fixed in various positions along the length of the shaft 1220. In some embodiments, a mechanism may be included to provide slight compression between the sleeve devices 1300a to 1300c and the shaft 1220 to adjustably fix the sleeve devices 1300a to 1300c in various positions along the length of the shaft 1220. For example, such a mechanism may include, but is not limited to, a clamp, an annular elastomer interface member, a wedge, a fastener, a jig, etc.

[0213] Each of the sleeve devices 1300a to 1300c defines one or more auxiliary working channels for receiving and guiding additional instruments. For example, sleeve device 1300a ( Figure 46 ) Defines a single auxiliary working channel 1320a. Sleeve device 1300b ( Figure 47 It also limits the single auxiliary working channel 1320b. Sleeve device 1300c ( Figure 48 The first auxiliary working channel 1320c and the second auxiliary working channel 1320d are defined.

[0214] The auxiliary working channel 1320a of the sleeve device 1300a is separated from the inner cavity 1312 through the material portion of the sleeve device 1300a, such as Figure 46 As shown. In contrast, the auxiliary working channel 1320b of the sleeve device 1300b merges with the inner cavity 1312 (open, continuous), as... Figure 47 As shown. The auxiliary working channels 1320c and 1320d of the sleeve device 1300c are separated from the inner cavity 1312, as follows. Figure 48 As shown. It should be understood that any arrangement and combination of arrangements can be conceived and are within the scope of this disclosure. The dimensions and cross-sectional shapes of the auxiliary working channels 1320a to 1320b can be made in any desired manner, but are not limited thereto.

[0215] Figure 49 The right TM30 is shown with overlapping lines and markings indicating the coordinates of a position around the tympanic ring 32 surrounding the tympanic membrane 30. The position on the tympanic ring 32 can be identified using an analogy to a clock face with the malleus at 12 o'clock, as shown in the figure.

[0216] TM30 is a thin, cone-shaped membrane that separates the outer ear from the middle ear. The tympanic membrane ring 32 is a thicker fibrocartilaginous ring surrounding TM30. Therefore, the tympanic membrane ring 32 provides strong, stable tissue for anchoring the TM port device.

[0217] Figure 50 An exemplary tympanic membrane port device 1400 is shown, which includes a laterally extending anchoring portion 1420 attached to a sleeve 1410. The sleeve 1410 defines a port 1412 that serves as a channel for the instrument described herein.

[0218] As further described below, the cannula 1410 may be located (implanted during surgery and subsequently removed) within the TM30 (allowing the instrument to pass through the TM30 via port 1412 during surgery), while the anchoring portion 1420 is positioned within the tympanic membrane ring 32. In this way, the strong tympanic membrane ring 32 can serve as a stable base for anchoring the port device 1400. Therefore, the anchoring portion 1420 transfers stress to the tympanic membrane ring 32, minimizing the stress on the TM30 itself when the instrument is used in port 1412.

[0219] The anchoring portion 1420 has a sharp tip 1422. When the tympanic port device 1400 is inserted into the TM30 and the tympanic ring 32, the tip 1422 can pierce through the tympanic ring 32. The lateral length of the anchoring portion 1420 can be made to any desired length. The length of the anchoring portion 1420 will help define the final position of the cannula 1410 in the TM30.

[0220] Although sleeve 1410 is depicted as having a cylindrical outer profile, sleeve 1410 is not limited to this outer shape. For example, in some embodiments, the outer profile of sleeve 1410 may be as follows: Figure 15 As shown elsewhere in this document. In some embodiments, the outer profile of the sleeve 1410 may be a truncated cone, hourglass, bow, etc. The port 1412 may also have various cross-sectional shapes. In some embodiments, the port 1412 is curved, rather than linear as shown.

[0221] Figure 51 The image shows a tympanic membrane 30 and a tympanic membrane ring 32, in which two tympanic membrane port devices 1400 are implanted. It can be seen that a cannula 1410 is positioned to provide a passage through the TM30, while an anchoring portion 1420 extends to and penetrates the tympanic membrane ring 32. Therefore, the tympanic membrane ring 32 provides a strong and stable anchoring for the tympanic membrane port devices 1400.

[0222] It is conceivable that the anchoring portion 1420 could be used to attach or pierce other components, such as an elastomeric or hydrogel ring covering the tympanic membrane ring 32. The elastomeric ring could be pressed down into the ear canal and placed on the tympanic membrane so that it expands back into its shape around the periphery of the membrane covering the tympanic membrane ring, thus eliminating the need for direct piercing or attachment to the tympanic membrane ring (and the potential pain associated with that step), while still allowing the port 1410 to be stabilized and anchored.

[0223] Figure 52 A tympanic membrane 30 and a tympanic membrane ring 32 with an implanted exemplary dual-port tympanic membrane port device 1500 are shown. The dual-port tympanic membrane port device 1500 includes a first tympanic membrane port device 1510a and a second tympanic membrane port device 1510b. Thus, two ports through the TM30 are provided by the dual-port tympanic membrane port device 1500.

[0224] Tympanic port devices 1510a and 1510b are connected to each other by a connecting member 1512. The connecting member 1512 can be of any desired length to establish a center-to-center distance between the two tympanic port devices 1510a and 1510b.

[0225] Figure 53The tympanic membrane 30 and tympanic membrane ring 32 of an exemplary dual-port tympanic membrane port device 1500 with another implant are shown. In this example, the tympanic membrane port device 1500 includes an anchoring portion 1520. The anchoring portion 1520 extends laterally from the tympanic membrane port device 1510b and pierces the tympanic membrane ring 32 (e.g., as described above with reference to the anchoring portion 1420 of the tympanic membrane port device 1400); Figure 50 and 51 It should be understood that the anchoring portion 1520 may extend laterally from the dual-port tympanic membrane port device 1500 in any desired direction. Although the depicted dual-port tympanic membrane port device 1500 includes a single anchoring portion 1520, in some embodiments, two or more of the anchoring portions 1520 may be attached to the dual-port tympanic membrane port device 1500. Thus, in some embodiments, the dual-port tympanic membrane port device 1500 may be anchored at two or more locations on the tympanic membrane ring 32 (attached to pass through TM30 at two locations).

[0226] Figure 54 A tympanic membrane 30 and a tympanic membrane ring 32 with an exemplary three-port tympanic membrane port device 1600 are shown. The three-port tympanic membrane port device 1600 includes a first tympanic membrane port device 1610a, a second tympanic membrane port device 1610b, and a third tympanic membrane port device 1610c. Each of the tympanic membrane port devices 1610a to 1610c defines a port through TM30.

[0227] The tympanic membrane port devices 1610a to 1610c are interconnected via a coupling member 1612. The coupling member 1612 can be of any desired shape and length to establish a center-to-center distance between the three tympanic membrane port devices 1610a to 1610c. In some embodiments, one or more anchoring portions (e.g., like anchoring portion 1520); Figure 53 It can be attached to the three-port tympanic membrane port device 1600 to facilitate the anchoring of the three-port tympanic membrane port device 1600 in the tympanic membrane ring 32.

[0228] In some cases, a third-port device can instead be a lens to allow visualization of the middle ear through the tympanic membrane using an operating microscope. This avoids the need for an endoscope, frees the surgeon's hands, and allows for binocular visualization. The lens can be convex to allow a wide field of view that is not achievable with an external microscope alone.

[0229] Figure 55 An exemplary endoscopic instrument 1700 is shown. The endoscopic instrument 1700 has a field of view extending from its tip at an angle α. The endoscopic instrument 1700 can be used, for example, transtympanicly, to visualize the middle and inner ear structures as described above.

[0230] In some cases, it is beneficial to expand the field of view of the endoscopic instrument 1700. For example, although the tip of the endoscopic instrument 1700 is located in the middle ear, it would be beneficial to expand the field of view of the endoscope due to the small and irregular shape of the middle ear.

[0231] Figure 56 The liquid lens 1730 is shown to be selectively generated at the tip of the endoscopic instrument 1700 to widen the field of view to an angle β (where β > α). For example, this liquid lens 1730 can be selectively generated when the tip of the endoscopic instrument 1700 is located in the middle ear. Refraction at the boundary between the liquid lens and air produces the optical effect of the lens.

[0232] Shaft 1720 may define a cavity 1722 through which liquid can be delivered to the tip of shaft 1720 to temporarily create a liquid lens 1730. The liquid may be, for example, a high-refractive-index liquid with a known surface tension to create a precisely sized droplet at the tip of the endoscopic instrument 1700. The size of the droplet can also be selectively adjusted to adjust the field of view (to adjust angle β). For example, the liquid lens 1730 may be eliminated by vibrating or erasing it from a tissue structure.

[0233] Figure 57 This is another exemplary embodiment including an inner cavity 1722 and a second inner cavity 1724. The second inner cavity 1724 can be used to aspirate liquid from the liquid lens 1730 to reduce the droplet size, or to eliminate liquid from the liquid lens 1730. As an exemplary benefit, the lens can be updated to remove any contamination from bleeding or surgery that might interfere with observation.

[0234] In some cases, ear surgery is performed while the space is submerged in fluid. For example, in some cases, ear surgery is performed when the middle ear and / or outer ear is submerged in fluid. In such cases, the endoscopic instrument 1700 may have an air bubble at the tip of the endoscope 1700 within a fluid-filled chamber to expand the field of view of the endoscope 1700.

[0235] In some embodiments, the middle ear can be visualized via an endoscope that captures images through the TM30. That is, the distal end of the endoscope may reside in the ear canal 20, and an image of the middle ear 40 may pass through the TM30 and be captured by the endoscope residing in the ear canal 20. In some embodiments, the image can be enhanced when an interface fluid is used between the lens at the endoscope tip and the TM30. For example, fluids such as Healon (sodium hyaluronate), silicone oil, glycerin, or hydroxymethylcellulose have been shown to be effective in enhancing image quality.

[0236] In some embodiments, the lens of the endoscope may be configured to enhance its ability to retain interfacial fluid. For example, the periphery may have edges or margins to help retain interfacial fluid. In some embodiments, the supply of interfacial fluid may be delivered to the tip of the endoscope using the lumen of the endoscope (e.g., controlled by a clinician to be continuous or intermittent).

[0237] refer to Figures 58-64 Specific embodiments of systems and methods for treating the ear may include an improved array of medical devices that provide enhanced visualization during minimally invasive, transtympanic access to structures in the middle or inner ear. The devices, systems, and methods described herein can be used to treat and / or prevent a variety of conditions, including but not limited to hearing loss, including latent hearing loss, noise-induced hearing loss, age-related hearing loss, drug-induced hearing loss (e.g., chemotherapy-induced hearing loss or aminoglycoside-induced hearing loss), sudden sensorineural hearing loss (SNHL), autoimmune inner ear diseases, etc.

[0238] While this article describes devices, systems, materials, compounds, compositions, articles, and methods primarily in the context of treating hearing loss, it should be understood that these devices, systems, materials, compounds, compositions, articles, and methods may also be used to treat any other conditions of the middle and / or inner ear, including but not limited to tinnitus, balance disorders including vertigo, Meniere's disease, vestibular neuronitis, vestibular auricular tumor, labyrinthitis, otosclerosis, ossicular chain dislocation, cholesteatoma, otitis media, middle ear infection, schwannoma, and tympanic membrane perforation, to provide a few examples.

[0239] This disclosure describes treatment methods and devices for treating patient 10 using minimally invasive methods. For example... Figure 58 In some embodiments, the access system described herein may be configured to deliver treatment to the cochlea via the patient's external auditory canal, for example, using various instruments further described below. In such embodiments, the instrument may be advanced through the tympanic membrane (TM), with one or more temporary support structures providing additional mechanical support to the tympanic membrane. In some cases, the distal portion of the instrument may be advanced into the middle ear and optionally toward a target anatomical structure (a non-limiting example includes the round window of the cochlea).

[0240] As described in more detail below, some instruments of the system may be configured to deliver a therapeutic agent to a target site in the ear. In some embodiments, the therapeutic agent delivered to the target site via a tympanic membrane instrument may be a semi-solid gel material. As a gel material, the delivery of the therapeutic agent may be maintained at the target site so that the therapeutic agent can gradually release its active ingredient over an extended period of time, such as days, weeks, or even months.

[0241] The following description (and in conjunction with) Figures 58-61 Other system improvements.

[0242] (1) Lighting and Visualization

[0243] refer to Figure 58 In some embodiments, the system includes one or more lighting and visualization instruments, such as a fixed “chandelier” illumination at or above the tympanic membrane (for use with a minimally invasive access system), a micro-camera, OCT, and observation via a TM microscope (with TM transparency increased, for example, by the application of glycerol or saline). In some embodiments, the endoscope has an illumination source.

[0244] In some embodiments, a so-called “chandelier” lighting device or light source may be applied or installed at or near the tympanic membrane without physically penetrating the membrane, while still allowing sufficient light to pass through the tympanic membrane to facilitate visualization of the middle ear structures.

[0245] In some embodiments, a solution or gel may be applied to the tympanic membrane to enhance its translucency and thereby increase the ability of external illumination (e.g., chandelier lighting) to penetrate the membrane. If the clarity or translucency is sufficiently enhanced, clinicians can visualize the middle ear structures directly through the membrane without having to physically insert an endoscope or other visualization instruments into the middle ear space. Glycerol or hypertonic saline is an example of such a solution or gel, which has been shown to enhance the optical clarity of collagen membranes. The gel or solution may be applied to the outer surface, inner surface, or both of the membrane using a small-diameter instrument.

[0246] Optical coherence tomography (OCT) is another visualization method that can be applied to facilitate visualization of the middle ear structure without the need for perforation or penetration of the tympanic membrane.

[0247] An alternative visualization modality can be positioned proximally on the axis or handle of the main endoscope or visualization device. This visualization device can assist clinicians in managing the interaction between the axis and the ear canal and can be displayed on the same observation monitor or mechanism as the main endoscope / visualization modality. This option reduces the need for “back and forth” use of the microscope and endoscope and provides closer observation of structures of interest.

[0248] In some embodiments, the stabilizer device described herein may include a camera device attached to the stabilizer device. In some embodiments, the TM port device described herein may include a light source, or may be transmissive to light. In some embodiments, dyes or other reagents may be used to improve contrast or highlight one or more specific target areas. In some embodiments, dual-wavelength or multi-wavelength illumination or visualization may be used to enhance visualization.

[0249] Even for otolaryngologists, one of the greatest challenges currently facing the use of endoscopes along pathways through the tympanic flap or transmastoid process is the typical binocular absence of microscopes, and the associated difficulty in instrument depth perception. Therefore, it can be argued that using depth markings on the axis of entry instruments would facilitate their use and adoption.

[0250] (2) Tympanic membrane reinforcement

[0251] In some embodiments, the system described herein may include one or more reinforcement structures for the TM, such as gels, tapes, or bandages, which are applied prior to TM perforation to prevent tearing and / or applied after TM perforation to repair / promote healing. One or more reinforcement structures may be applied directly to or adjacent to the TM. Optionally, one or more reinforcement structures may be combined with or integrated with an intubation cannula or canal-based fixation.

[0252] For example, the reinforcement structure may include a liquid or gel formulation, which may be deposited on the surface of the tympanic membrane and then applied to a localized area (approximately 0.2-5 mm). 2 Gels or polymers are used to increase penetration or adhesion for entry into the same area. Such reinforcing gels can mechanically support the membrane to reduce the likelihood of tympanic membrane tearing during perforation or insertion of visualization or entry instruments, and during manipulation tools that can subsequently apply lateral forces (in the plane of the tympanic membrane). Visualization or entry instruments may require long handles and shafts to navigate the ear canal and outer ear, and these long shafts or handles may have the potential to act as long lever arms, which could allow clinicians to inadvertently apply forces sufficient to tear the tympanic membrane while pursuing visualization or entry or performing other therapeutic interventions in the middle or inner ear. Thermogelling poloxamer is an example of a gel that has been shown to be compatible with the tympanic membrane. Alternatively, cross-linked PEG-based gels with higher mechanical strength can be used. Examples may include materials for wound closure such as DuraSeal, CoSeal, and Adherus.

[0253] Optionally, this topical gel can be removed immediately after surgery by mechanical dissection or by using an agent that is set / selected to break down the gel. Alternatively, the reinforcing gel can be left in place post-operatively to reinforce the membrane and thus promote healing. The gel may have self-sealing properties, which will enhance the ability of the sides of the tympanic membrane perforation to reconnect and thereby promote healing. In some options, the gel may also include one or more anesthetic agents, such as lidocaine, to relieve pain during or after surgery. Additionally, the gel may include supplements, such as antibiotics or steroids (e.g., dexamethasone), which improve healing at the tympanic membrane without requiring systemic or frequent topical application.

[0254] In another example, the reinforcement structure may include an adhesive tape material applied to the tympanic membrane to facilitate perforation or entry through the membrane while controlling local tearing forces or otherwise reducing the likelihood of tearing. The reinforcement tape may be applied to promote postoperative or post-entry healing. Examples of reinforcement tape materials may include porous filamentous biomaterials (layered porous membranes and electrospun nanofibers), polymeric foams, polymeric hydrogels, polymeric alginates, and polymeric hydrocolloids. In some cases, arrays of microneedles, microfeatures, etc., may be used on the tape structure to enhance adhesion of the tape to the tympanic membrane.

[0255] In some embodiments, the reinforcement structure may include a caustic agent for transiently and locally altering the tympanic membrane material. In this case, the agent may be configured to allow alteration of a local area (approximately 0.2-5 mm²) to enhance penetration or adhesion to enter within the same area. In one example, the caustic agent may include phenol for providing this caustic effect on the tympanic membrane.

[0256] (3) Fixation based on the ear canal and adjacent TM (in the outer ear);

[0257] refer to Figure 59 In some embodiments, the system includes one or more fixation structures that can be positioned in the ear canal to provide support for instruments during transtympanic access surgery. Such fixation structures may include an inflatable “balloon” wall, a telescopic “finger mesh” / support structure, a ring, and an improved endoscope with an instrument fixation ring near the TM, wherein the ring is configured to be anchored adjacent to the TM and equipped with a mesh or transparent mesh material for supporting instruments passing through the ring.

[0258] For example, the local reinforcement formulations or agents discussed above (such as reinforcement gels) can be used across the entire length of the tympanic membrane to hold the perforation or entry site in place relative to the ear canal walls and edges of the tympanic membrane. This transtympanic fixation or stabilization has the potential advantage of significantly reducing lateral forces at the entry site, which is particularly advantageous during procedures where clinicians manipulate instruments or visualization tools. In certain embodiments, the gel is substantially translucent to allow direct visualization of the tympanic membrane.

[0259] Alternatively, this fixation or stabilization can be used in place of local reinforcements (such as gel, cannula, or grommets) or in any combination with these local reinforcements. It can also be considered that stabilization or fixation does not need to cover the entire tympanic membrane and can cover “X” shapes, line intersections, or other shape variations to secure the entry site in place.

[0260] In some embodiments, the mesh can similarly serve as a stabilizer or fixation. This mesh can be placed adjacent to the tympanic membrane. Entry or perforation of the tympanic membrane can be made through holes in the mesh, and the entry site is prevented from lateral movement by the strands of the mesh. This mesh can be combined with gels or other reinforcement or adhesion methods. This mesh can be constructed from polymers (e.g., polypropylene, nylon, or others), elastomers (e.g., polyurethane or silicone), or fabrics. Optionally, the mesh can be substantially translucent to allow direct visualization of the tympanic membrane.

[0261] In other embodiments, an inflatable balloon wall with a central member can be considered to similarly provide fixation of the entry point to the appropriate location. Such a balloon can be annular (similar to the inner tube of a tire), with reinforcing members spanning the surface of its inner cavity region. A mesh can also be suspended across the inner cavity region. It can be considered that the "ring" of the balloon can consist of a series of smaller, compliant or non-compliant balloons, allowing the inner cavity region to avoid blockage under high pressure.

[0262] In certain embodiments, an improved speculum with a fixation device at its distal end can be used in the ear canal to provide fixation or stabilization of the distal end of the speculum adjacent to the tympanic membrane.

[0263] In another embodiment, a support device with a "cupcake package" structure (e.g., optionally including a series of folds or pleats in a conical cylinder) can be inserted into the ear canal to provide fixation or stability relative to the ear canal. The folds and pleats will allow the device to conform to or fit a range of ear canal sizes and shapes. It may have a mesh, gel, membrane, or other material across the distal end to ensure fixation at the insertion site. Such embodiments offer the additional potential advantage of protecting the ear canal walls from accidental impacts or damage. Some patients are highly sensitive to impacts to the ear canal walls and may flinch or otherwise interfere with the procedure.

[0264] In another embodiment, a tube of flexible or elastomeric, gel, or soft or deformable material may be lined to the ear canal wall to protect it from impact or damage during visualization or access. It is conceivable that such a tube can be combined with the stabilizing or fixing mesh or ring, balloon, or any other fixation method discussed.

[0265] It is understandable that methods of fixing or stabilizing adjacent tympanic membranes can also be used in combination or as mounting methods for visualization or lighting.

[0266] Figure 72 and 73 An exemplary non-penetrating port device 2200 is shown that can be placed adjacent to the TM30. The non-penetrating port device 2200 defines one or more ports 2210 (one port 2210 is included in this example) through which any type of instrument (including an endoscope) described herein can pass.

[0267] In some embodiments, one or more ports 2210 include orientation features, such as slots or keyways for orienting instruments passing through the one or more ports 2210. For example, in some embodiments, an instrument used with a particular port 2210 (e.g., an endoscope, but not limited thereto) may have an outer profile that matches the inner profile of the particular port 2210 (e.g., a key in a keyway). In this way, orientation of instruments passing through the one or more ports 2210 can be established and maintained.

[0268] The non-penetrating port device 2200 includes two or more legs or features 2220 (three legs 2220 in this example). The legs extend to feet 2222. In some embodiments, feet 2222 may be releasably attached to TM30. In a particular embodiment, feet 2222 may be releasably attached to a tympanic membrane ring 32 surrounding the tympanic membrane 30. This can help increase the stability of the port 2210. It can also facilitate the easy establishment of a positional distance between the port 2210 and the tympanic membrane ring.

[0269] In some embodiments, the foot 2222 is releasably attached to the TM30 or the tympanic ring 32 using an adhesive 2224. Alternatively, in some embodiments, the non-penetrating port device 2200 may be attached to the axis of an instrument (e.g., an endoscope, but not limited thereto) and the foot 2222, wherein the foot 2222 is formed to gently abut the TM30 or the tympanic ring 32. In this way, the non-penetrating port device 2200 can be used as a depth limiting and stabilizing device.

[0270] In some embodiments, two or more legs 2220 are arranged symmetrically. Alternatively, in some embodiments, two or more legs 2220 are arranged asymmetrically, as in the depicted embodiments. In some embodiments, two or more legs 2220 include portions that make the two or more legs 2220 flexible. In some cases, this flexibility of the two or more legs 2220 may help prevent excessive pressure from being applied to the TM30.

[0271] Figure 74Another non-penetrating port device 2300 is shown, which can be placed in and / or adjacent to the external auditory canal 20 and TM30. The non-penetrating port device 2300 has a port member 2310 defining one or more ports 2312 (two ports 2312 are present in this example). The non-penetrating port device 2300 also has two or more radially expandable arms 2320 attached to the port member 2310 (two arms 2320 are present in this example). The arms 2320 can be of the same length or different lengths, such that the port device 2300 or channel can be off-center positioned or positioned at a designated location (if desired), which can facilitate, for example, establishing a channel in the posteroinferior region of the tympanic membrane ring. Various arm shapes, legs, or spring-like features are contemplated for maintaining port position. It is also contemplated that the arms or legs may have foot-like features extending to their respective distal tips or along their length to help secure the assembly in place or help distribute outward forces over a larger area.

[0272] It is understandable that having a port adjacent to, but not necessarily in contact with, the TM30 can facilitate the stability of any instrument passing through an incision or hole in the TM30, while minimizing contact with the fragile rest of the TM30. Such a port can also be advantageous due to its use of the stable ear canal structure to maintain position.

[0273] During delivery of the non-penetrating port device 2300 into the ear canal 20, the radially expandable arm 2320 retracts radially near the port member 2310. After achieving the desired positioning within the ear canal 20, the radially expandable arm 2320 can then be allowed to expand radially outward to abut against the wall of the ear canal 20. In this way, the non-penetrating port device 2300 is temporarily secured in place within the ear canal 20.

[0274] Figure 75 Another non-penetrating port device 2400 is shown, which can be placed in and / or adjacent to the external auditory canal 20 and TM30. The non-penetrating port device 2400 is a wire looped to define one or more ports 2412 (four ports 2412 are present in this example). Alternatively, a spring-like wire can be slidably attached (in all four positions of the depicted port device 2400) to... Figure 74 The port shown is similar to the port shown, and the spring-shaped feature can be used instead of an arm to fix the port against the ear canal wall.

[0275] During delivery of the non-penetrating port device 2400 into the ear canal 20, the non-penetrating port device 2400 contracts radially. After achieving the desired positioning within the ear canal 20, the non-penetrating port device 2400 may then be allowed to expand radially outward against the wall of the ear canal 20, forming one or more ports 2412. In this way, the non-penetrating port device 2400 is temporarily secured in place within the ear canal 20.

[0276] (4) External fixing

[0277] refer to Figure 60 In some embodiments, the system includes an external fixation structure that can be positioned outside the ear canal to provide support for the access instrument during transtympanic access surgery. For example, an improved otoscope with a fixation support located at the ear canal opening can be used to provide additional support and / or stability for the access instrument.

[0278] In some embodiments, the influence of an instrument or endoscope on the lateral movement or position of the access site on the tympanic membrane can be controlled by controlling the movement of the handle or shaft of the instrument or endoscope at the outer ear via a stabilizing or fixing device or apparatus. Such a device may be mounted in the ear canal adjacent to the outer ear or mounted on the outer ear itself. The device may optionally be transparent to minimize interference with microscopic or naked-eye visualization of the ear canal. Alternatively, the device may be equipped with its own camera embedded at its distal end to provide visualization of the ear canal.

[0279] This device allows control over the degree of freedom and range of motion of the axis of the imported or visualized instrument. In some implementations, notches, slots, or screw-in stopcocks can be used to restrict the movement of the instrument's axis. In some procedures, the device can be equipped with a lock to secure the endoscope or other viewing equipment in place after the desired view has been achieved. This configuration frees up one hand for the clinician and allows for two-handed operation of instruments used for delivery, aspiration, pseudomembrane removal, or other tissue manipulation in the middle ear. This is particularly advantageous for clinicians who are accustomed to using both hands to operate instruments and have a hand preference for certain tools, regardless of which ear is being worked on.

[0280] In some embodiments, stimulus-responsive polymers may be integrated into local or external reinforcements to provide an "early warning" of higher forces that could cause tearing or damage to the tympanic membrane.

[0281] This fixation device can be considered to aid in the registration of the position of the handle of the imported or visualized instrument, and thereby aid in the registration of the insertion or entry point in the tympanic membrane. This can help ensure that subsequent entry procedures consistently use the entry point of the previous procedure, or avoid the entry point of the previous procedure. Some middle ear procedures envisioned in this article (including regular delivery of therapeutic agents) may involve repeated trans-tympanic membrane entry on a weekly, monthly, quarterly, semi-annual, or annual basis. Therefore, the solution described in this article reduces the likelihood of permanent scarring of the tympanic membrane, which could otherwise affect repeated trans-tympanic membrane entry.

[0282] Similarly, the system can be used to advantageously visualize the tympanic membrane and then mark it to highlight the desired entry point for subsequent insertion of an instrument through the membrane.

[0283] (5) Middle ear fixation

[0284] In some embodiments, the system includes one or more middle ear fixation elements for providing support for access instruments during transtympanic access surgery. For example, one or more middle ear fixation elements may include an expanded material deposited in the middle ear to reinforce the tympanic membrane, such as… Figure 61 As shown.

[0285] For example, the middle ear may be temporarily filled with a translucent gel or polymer (e.g., poloxamer gel or PEG), which fills the middle ear and acts as a support for the axis of the insertion and / or visualization instrument. In this case, the tympanic membrane itself acts as part of the sealing mechanism to hold the gel in place. The eustachian tube or ear canal will serve as another exit from the middle ear and can also serve as a natural, gradual removal mechanism for the gel or temporary polymer.

[0286] Optionally, the gel can be photocurable, and as the endoscope is slowly retracted away from the desired delivery point (e.g., a round window membrane), a light source at the endoscope tip can be used to selectively cure a thin-walled channel through the gel, thereby creating a channel through the gel that can be used to deliver the therapeutic agent to the delivery point (e.g., the round window membrane). The agent can then be photocured at the desired location. The channel and body of the gel will then degrade and be carried away through the Eustachian tube.

[0287] Alternatively, a device at the ear canal exit to the outside of the ear canal can be used to provide a seal or containment of a translucent gel or temporary polymer (e.g., poloxamer gel or PEG), wherein the gel fills the ear canal and acts as a support for the axis of the inlet and / or visualization instrument. Depending on the patient and the orientation of their ear canal, the gel can be placed in the ear canal and remain in place without sealing or containment.

[0288] In some embodiments, the fluid or gel in the middle ear used for “underwater surgery” can be used to pack away bleeding, improve TM visualization, and / or provide support for instruments, among other advantages. In some embodiments, the external auditory canal can also be filled (or partially filled) with fluid or gel. In some embodiments, pathways can be created in a solidified gel, which can serve as a channel or cavity for substances delivered along with therapeutic agents.

[0289] refer to Figure 62 The image shows a cross-sectional view of an exemplary endoscope axis 1800. In this example, the outer contour of the endoscope axis 1800 is circular in cross-section.

[0290] The endoscope axis 1800 defines a concentrically positioned working channel 1810. The instruments described in this disclosure can be slidably advanced within the working channel 1810. Although the depicted working channel 1810 has a circular cross-sectional shape, in some embodiments, other shapes may be defined by the working channel 1810, such as, but not limited to, oval, elliptical, polygonal, etc. In some embodiments, the endoscope axis 1800 may define two or more working channels 1810.

[0291] The endoscope axis 1800 also includes illumination 1820 (e.g., fiber optic elements, LEDs, and / or combinations thereof) and fiber optic cable 1830 for image capture. As shown, in some embodiments, these may be arranged in an arcuate pattern (in cross-section). Other geometric arrangements are also envisioned, such as, but not limited to, circular, oval, linear, polygonal, etc.

[0292] refer to Figure 63 The image shows a cross-sectional view of another exemplary endoscope axis 1900. In this example, the outer contour of the endoscope axis 1900 is oblong in cross-section.

[0293] Endoscope axis 1900 defines a working channel 1910 offset from the geometric center of endoscope axis 1900. While the depicted working channel 1910 has a circular cross-sectional shape, in some embodiments, other shapes may be defined by the working channel 1910, such as, but not limited to, oval, elliptical, polygonal, etc. In some embodiments, endoscope axis 1900 may define two or more working channels 1910.

[0294] The endoscope axis 1900 also includes an illumination element 1220 (e.g., one or more fiber optic elements, one or more LEDs, and / or combinations thereof) and an image capture element 1930 (e.g., a camera, fiber optics, and combinations thereof). As shown, in some embodiments, two image capture elements 1930 are present. Alternatively, in some embodiments, a single image capture element 1930 and two illumination elements 1920 are present.

[0295] Also refer to Figure 64 The distal portion of endoscope axis 2000 is shown. Endoscope axis 2000 defines a working channel 2010, which in this example will slidably receive an exemplary instrument 2040. This illustration clearly shows that the inlet and outlet of working channel 2010 can be anywhere along axis 2000. For example, in the depicted arrangement, working channel 2010 extends only a short distance along the distal portion of endoscope axis 2000. Therefore, any working channel described herein can be configured with an outlet and an inlet located anywhere along the axis of the endoscope.

[0296] Figure 65 A portion of another type of shaft 2100 is shown, which defines a working channel 2110. In this example, the working channel 2110 is C-shaped in cross-section. That is, the opening portion of the working channel 2110 extends longitudinally along the shaft 2100. In other words, in this example, the working channel 2110 is a top-open channel. Additionally, in some embodiments, one or more openings 2112 (optional) are included as openings in the working channel 2110. The opening of the working channel 2110 can facilitate the sterilization of the long, narrow working channel 2110. That is, sterilizing gases and / or vapors can enter and exit the long, narrow working channel 2110 to a greater extent due to its openness.

[0297] Figure 66 Show Figure 55 Another exemplary distal tip portion of the shaft 1720 of the illustrated endoscopic instrument 1700. In this example, shaft 1720 includes a proximal shaft portion 1726 and a distal shaft portion 1728. The distal shaft portion 1728 extends distally from the proximal shaft portion 1726. In some embodiments, the central longitudinal axes of the proximal shaft portion 1726 and the distal shaft portion 1728 are collinear. In some embodiments, the central longitudinal axes of the proximal shaft portion 1726 and the distal shaft portion 1728 are parallel but offset from each other. In some embodiments, the central longitudinal axes of the proximal shaft portion 1726 and the distal shaft portion 1728 are oblique lines or non-parallel intersecting lines.

[0298] The cross-sectional dimensions of the distal shaft portion 1728 are smaller than those of the proximal shaft portion 1726. For example, in some embodiments, the ratio of the external dimensions of the distal shaft portion 1728 to those of the proximal shaft portion 1726 is between 0.1:1 and 0.8:1, or between 0.2:1 and 0.7:1, or between 0.3:1 and 0.6:1, or between 0.4:1 and 0.5:1, but is not limited thereto.

[0299] While the depicted embodiments show an abrupt change in external dimensions between the proximal shaft portion 1726 and the distal shaft portion 1728, in some embodiments, a gradual change, such as a tapered portion, is used.

[0300] In some embodiments, the longitudinal length of the distal shaft portion 1728 is between 4 mm and 20 mm, or between 6 mm and 18 mm, or between 8 mm and 14 mm, or between 10 mm and 12 mm, or between 6 mm and 14 mm, or between 8 mm and 12 mm, but is not limited thereto.

[0301] The distal tip portion of the depicted axis 1720, including the smaller distal axial portion 1728, may facilitate at least some of the therapeutic procedures described herein. For example, in some cases, only the smaller distal axial portion 1728 passes through the TM. That is, in some cases, the transition between the proximal axial portion 1726 and the distal axial portion 1728 may be positioned adjacent to the TM, and only the smaller distal axial portion 1728 passes through the TM (e.g., using a TM port device, via a puncture / incision in the TM, or through an area of ​​the TM that has been opened using any other technique). Thus, in some embodiments, a smaller opening may be formed through or around the TM (compared to a conventional endoscope typically along a single axial dimension). In some embodiments, a non-invasive buffer element may be included at the transition between the proximal axial portion 1726 and the distal axial portion 1728, such that the TM is protected from damage if it comes into contact with the transition.

[0302] Furthermore, in some cases, the transition between the proximal axis portion 1726 and the distal axis portion 1728 can be advantageously used to limit or control the depth of insertion of the endoscope axis 1720 into the middle ear. This arrangement (where the proximal axis portion is larger than the distal axis portion) can also be used with other types of instruments described herein, but is not limited thereto.

[0303] In some cases, a tapered or non-uniform shaft outer diameter with proximal shaft portion 1726 and distal shaft portion 1728 allows for greater stiffness while being easier to manufacture. As an example, a smaller diameter distal portion can be more fragile, especially over longer lengths. A larger proximal diameter reduces the portion of the component that is more susceptible to damage. In some embodiments, the distal shaft portion 1728 can be made to have greater flexibility (less stiffness) to reduce the lateral forces that can be applied to the TM by the distal shaft portion 1728 (and reduce the likelihood of tearing or otherwise damaging the TM). Greater flexibility can also be achieved by using a different material to encase the distal shaft portion 1728, thus achieving less stiffness.

[0304] Although in the depicted embodiment, light emitted from shaft 1720 is projected from the distal end of distal shaft portion 1728, in some embodiments, light may alternatively or additionally be projected from the distal end of proximal shaft portion 1726 (e.g., at the transition between proximal shaft portion 1726 and distal shaft portion 1728). That is, in some cases, light emitted from shaft 1720 is projected from the distal end of proximal shaft portion 1726 located in the ear canal (or outside the TM). In this case, light can penetrate through the TM and into the middle ear.

[0305] In some embodiments, the proximal shaft portion 1726 may include a working channel, for example, similar to... Figure 64 As shown.

[0306] Although in the depicted embodiments, the image observed by the endoscope is captured at the distal end of the distal axis portion 1728, in some embodiments, the image observed by the endoscope is at the distal end of the proximal axis portion 1726 (e.g., at the transition between the proximal axis portion 1726 and the distal axis portion 1728, such as...). Figure 77 (As shown) captured. In some embodiments, the two images are observed by an endoscope, for example at the distal end of the distal axial portion 1728 and the distal end of the proximal axial portion 1726.

[0307] Also refer to Figure 67 In some embodiments, the distal shaft portion 1728 may retract and extend from the distal end of the proximal shaft portion 1726. For example, in Figure 65 In the middle, the distal shaft portion 1728 is retracted distally relative to the proximal shaft portion 1726, and... Figure 66 In this embodiment, the distal axial portion 1728 extends distally relative to the proximal axial portion 1726. In such embodiments, the clinical operator of the endoscope can controllably extend the distal axial portion 1728 from the distal end of the proximal axial portion 1726 to any desired length ranging from about 0 mm to about 20 mm or greater. In some embodiments, markings may be included on the endoscope to visually indicate the distance the distal axial portion 1728 extends distally from the proximal axial portion 1726.

[0308] Also refer to Figure 68In some embodiments, the distal shaft portion 1728 may retract and extend distally from the proximal shaft portion 1726, and the distal shaft portion 1728 is curved or may be curved. In some embodiments, the distal shaft portion 1728 is naturally curved such that it exhibits a curve as it extends distally from the proximal shaft portion 1726. In some embodiments, the distal shaft portion 1728 may also rotate relative to the proximal shaft portion 1726. Thus, by controllably rotating and / or extending the distal shaft portion 1728 relative to the proximal shaft portion 1726, clinicians can effectively position the distal tip of the distal shaft portion 1728 in a variety of positions and orientations.

[0309] In some embodiments, the distal axis portion 1728 is controllably deflectable or steerable (e.g., using internal control lines, using one or more internal axes, etc.). In this case, the distal axis portion 1728 may be linear, as desired by the clinical operator of the endoscope. Figure 66 ) or curved (e.g., Figure 68 In such embodiments, the distal shaft portion 1728 may be retracted and extended from the distal end of the proximal shaft portion 1726, or the distal shaft portion 1728 may be fixed relative to the distal end of the proximal shaft portion 1726.

[0310] In some embodiments, the endoscopes described herein (e.g., Figures 55-57 and Figures 66-68 The endoscopic instrument 1700 may include indicators on the handle and / or axis to help the clinical user mentally visualize the orientation of the distal axis portion 1728. Such markings can be used to help the clinical user better understand the orientation of the images captured by the endoscope and displayed on a screen. In short, the markings can help the clinical user understand which direction is up, etc. Such markings can be purely visual, tactile (e.g., one or more raised or recessed areas on the handle), or combinations thereof. In some embodiments, tactile markings (e.g., ridges, bumps, etc.) on the handle of the endoscope can be used to rotate the distal axis portion 1728. In some embodiments, the markings may also be displayed on a screen used to view images captured by the endoscope to help indicate orientation on the screen.

[0311] In certain embodiments, one or more gyroscope devices may be incorporated into the endoscope described herein. Such gyroscope devices may also be used to indicate the orientation of the endoscope axis and the image (e.g., which direction is upward), or combined with image processing to always display the image on the screen "up" relative to gravity.

[0312] Also refer to Figure 69 and 70In some embodiments, the distal shaft portion 1728 is detachable from the distal end of the proximal shaft portion 1726. Various types of mechanisms can be used for releasably engaging the distal shaft portion 1728 to the distal end of the proximal shaft portion 1726. For example, in the depicted embodiment, the distal shaft portion 1728 includes a protrusion 1729 that engages in a corresponding recess 1727 defined by the distal end of the proximal shaft portion 1726. Thus, in some embodiments, the distal shaft portion 1728 can be snapped into engagement with the proximal shaft portion 1726. Other types of mechanisms can be used for releasably engaging the distal shaft portion 1728 to the distal end of the proximal shaft portion 1726, such as, but not limited to, threaded connections, collet connections, bayonet connections, etc.

[0313] In some embodiments, the removable distal shaft portion 1728 is a single-use, disposable article. Alternatively, in some embodiments, the removable distal shaft portion 1728 is a multi-purpose, sterilizable article.

[0314] In some embodiments, as depicted, the proximal end of the removable distal shaft portion 1728 is received within a receptacle defined by the distal end of the proximal shaft portion 1726. In some such embodiments, the proximal shaft portion 1726 may include a lens that receives an image captured by the removable distal shaft portion 1728.

[0315] refer to Figure 71 Further endoscopic features are contemplated within the scope of this disclosure. In the depicted embodiment, the distal axis portion 1728 includes one or more fiber optic elements, glass, or other high optical transmittance elements that transmit images to a lens 1740 within the proximal axis portion 1726. The lens 1740 then transmits the image to a nearby CCD camera 1750 located within the proximal axis portion 1726. The CCD camera 1750 may be larger than its size if located in the distal axis portion 1728. The CCD camera 1750 is operatively connected to an image processor 1760, which may be located in the proximal axis portion 1726 or in another, more proximal portion of the endoscope.

[0316] The depicted arrangement offers numerous advantages. For example, the relatively short length of one or more fiber optic elements feeding the image into the distal axial portion 1728 of lens 1740 allows for a smaller distal axial portion 1728 with only a slight loss of image resolution along its length. This also corresponds to lower manufacturing costs, as longer fibers with a given level of signal quality are more expensive. In other words, the depicted arrangement allows the smaller distal axial portion 1728 to achieve the same resolution as a larger diameter endoscope, since signal loss is typically overcome by having more fibers. Furthermore, making the processing of the digital image at image processor 1760 relatively close to that of CCD camera 1750 again reduces signal loss.

[0317] refer to Figure 76 In some cases, the procedures described herein may be performed using two endoscopes. For example, as depicted, a first endoscope 1700a may be positioned in the ear canal 20 with a view of TM30, and a second endoscope 1700b may extend through TM into the middle ear 40. The first endoscope 1700a may be used to visualize the second endoscope 1700b (and / or other instruments) as the second endoscope 1700b (and / or other instruments) is advanced through TM30. In some embodiments, the first endoscope 1700a may be a light source for the second endoscope 1700b. One or both of the endoscopes 1700a-b may be stabilized using any of the stabilizing devices described herein.

[0318] In some embodiments, the first endoscope 1700a may have binocular vision. In a particular embodiment, the second endoscope 1700b may have binocular vision. In some cases, both of the endoscopes 1700a-b may be advanced through the TM30 into the middle ear 40.

[0319] refer to Figure 77 In some embodiments, a single axis 1720 of the endoscope 1700 may include two locations where images are captured. For example, in the depicted embodiment, a first image is captured at the transition between the proximal axis portion 1726 and the smaller distal axis portion 1728. This provides a view of the TM30 from the ear canal 20. A second image is captured at the distal end of the distal axis portion 1728. This provides a view of the middle ear 40. In some embodiments, a single light source may be mounted at the transition between the proximal axis portion 1726 and the smaller distal axis portion 1728. The single axis 1720 may be stabilized by any of the stabilization devices described herein.

[0320] When two images are captured, for example by Figure 76 and 77For example, the two images can be displayed on a single screen or on two separate screens. When the two images are displayed on a single screen, the images can be adjusted / configured by the clinical user. For instance, the images can be sized and positioned on the screen according to the clinical user's preferences. The screen and / or endoscope may also include orientation markers as described above. It is conceivable that simultaneous visualization at different depths will be beneficial for use with other middle ear surgeries, such as, but not limited to, cholesteatoma resection, tympanotomy, stapes reconstruction, or other procedures.

[0321] Figure 78 and 79 An exemplary substance delivery and aspiration device 2500 (or simply "device 2500") is shown. Device 2500 includes a spindle 2510. Device 2500 also includes a substance delivery conduit 2520 and an aspiration conduit 2530. The substance delivery conduit 2520 and the aspiration conduit 2530 extend distally from the spindle 2510.

[0322] In some embodiments, the substance delivery catheter 2520 and the aspiration catheter 2530 are extendable and retractable (individually or jointly) relative to the main axis 2510. The substance delivery catheter 2520 and the aspiration catheter 2530 may be flexible and conformably compliant with the tissues of the ear (including the middle and inner ear) in a trauma-resistant manner.

[0323] Device 2500 has various uses. In the depicted example, device 2500 is used to deliver a substance (e.g., one or more therapeutic agents) into the inner ear (via round window 52) and aspirate fluid from the inner ear. In some embodiments, delivery and aspiration are performed completely or at least partially simultaneously. Alternatively, in some embodiments, delivery and aspiration are performed at different times. Such devices can be used for temporary or long-term purposes.

[0324] While this article describes devices, systems, materials, compounds, compositions, articles, and methods primarily in the context of treating hearing loss, it should be understood that these devices, systems, materials, compounds, compositions, articles, and methods may also be used to treat any condition of the middle and / or inner ear, including but not limited to tinnitus, balance disorders including vertigo, Meniere's disease, vestibular neuronitis, vestibular auricular tumor, labyrinthitis, otosclerosis, ossicular chain dislocation, cholesteatoma, otitis media, middle ear infection, and tympanic membrane perforation, to provide a few examples.

[0325] While the round window membrane is one target site for therapeutic agent delivery or access, the systems and methods described herein can also be used to precisely deliver therapeutic agents to other target sites (e.g., the elliptical window or other parts of the middle ear cavity) and to provide access to other features or regions of the middle ear. For example, the systems and methods described herein can be used for minimally invasive surgical reconstruction of the ossicular chain, for cholesteatoma removal, for diagnostic evaluation, and other surgical procedures. Any and all such techniques used with the systems and methods described herein are included within the scope of this disclosure.

[0326] The apparatuses, systems, materials, compounds, compositions, articles, and methods described herein can be understood by referring to the above detailed description of specific aspects of the disclosed subject matter. However, it should be understood that the foregoing aspects are not limited to specific apparatuses, systems, methods, or reagents, and are therefore subject to variation. It should also be understood that the terminology used herein is for the purpose of describing specific aspects only and is not intended to be limiting.

[0327] Many embodiments have been described. However, it should be understood that various modifications can be made without departing from the scope of this disclosure. Therefore, other embodiments are within the scope of the appended claims.

Claims

1. A system for delivering a therapeutic gel formulation into a round window niche of the cochlea under direct endoscopic visualization, the system comprising: A sleeve device, defined as: a main channel and an auxiliary working channel, the main channel having a first diameter and extending to the distal end of the sleeve device, the auxiliary working channel having a second diameter smaller than the first diameter and being laterally separated from the main channel by a middle wall portion of the sleeve device, such that the central longitudinal axis of the auxiliary working channel is not parallel to the central longitudinal axis of the main channel. An endoscope having an endoscope axis sized to extend through the main channel of a sleeve device, such that when the sleeve device is outside the tympanic membrane, the distal portion of the endoscope can be positioned through the tympanic membrane and enter the middle ear to visualize the circular window niche of the cochlea. and An otological syringe device includes: a syringe containing a therapeutic gel formulation comprising an anti-inflammatory agent; and a syringe shaft connected to the syringe, and slidable through an auxiliary working channel of the sleeve device when an endoscope shaft is positioned within a main channel of the sleeve device. The distal tip of the syringe shaft is positioned through the tympanic membrane and is movable distal to a distal portion of the endoscope, such that the distal tip of the syringe shaft can advance into a circular window niche to deliver the therapeutic gel formulation into the niche, while the distal portion of the endoscope is proximally spaced from the distal tip of the syringe shaft to provide visualization of the syringe shaft. The non-parallel relationship between the auxiliary channel and the main channel is oriented to reduce the effective diameter of the endoscope shaft and the syringe shaft passing through the tympanic membrane. The syringe shaft includes a first curved portion and a second curved portion, the second curved portion being curved in the opposite direction to the first curved portion, and the first curved portion and the second curved portion having shape memory.

2. The system according to claim 1, wherein, The non-parallel relationship is defined by an angle between 0° and 20°.

3. The system according to claim 2, wherein the non-parallel relationship is defined by an angle between 0° and 10°.

4. The system according to claim 1, wherein, The distal tip of the syringe shaft terminates at a tilted distal tip, which defines a port through which the therapeutic gel formulation is ejected.

5. The system of claim 1 further includes a membrane modification device, which can be actuated to tear open the dummy membrane at the circular window niche while the distal portion of the endoscope in the middle ear is spaced apart from the membrane modification device and visualization of the membrane modification device is provided.

6. The system according to claim 1, wherein, The therapeutic gel formulation including the anti-inflammatory agent comprises a first functional component and a second functional component, the first functional component and the second functional component being mixed within the syringe to produce a gel crosslinking reaction.

7. The system according to claim 6, wherein, The therapeutic gel formulation contained in the syringe comprises an anti-inflammatory agent selected from the group consisting of: Hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone acetonide, medicone, prednisolone, prednisolone 21-phosphate, prednisolone acetate, flumethasone, betamethasone, and triamcinolone.

8. The system according to claim 6, wherein, The anti-inflammatory agent in the therapeutic gel formulation is provided in an amount sufficient to passively move through the membrane of the circular window and into the cochlea via diffusion.

9. The system according to claim 1, wherein, The syringe shaft of the otolaryngology syringe device includes a flexible distal tip.

10. The system according to claim 1, wherein, The syringe shaft extends from the distal end of the sleeve device and is not parallel to the central longitudinal axis of the main channel at the distal end of the sleeve device.

11. The system according to claim 1, wherein, The otological syringe device also includes a sheath, wherein, during the advance through the tympanic membrane, the distal end of the syringe shaft can be positioned within the cavity of the sheath.

12. The system of claim 1, further comprising at least one tympanic membrane port device configured to be removably implanted into a patient's tympanic membrane, the tympanic membrane port device comprising a central cavity with a diameter of 1 mm.

13. The system according to claim 1, wherein, The sleeve device is configured to press against the outside of the endoscope to secure the sleeve device to the endoscope when the endoscope shaft is positioned using the main channel, such that the distal tip of the syringe shaft is movable relative to the sleeve device and the distal portion of the endoscope.

14. A system for delivering a therapeutic gel formulation into a round window niche of the cochlea under direct endoscopic visualization, the system comprising: A sleeve device, defined as: a main channel and an auxiliary working channel, the main channel having a first diameter and extending to the distal end of the sleeve device, the auxiliary working channel having a second diameter smaller than the first diameter and laterally positioned adjacent to the main channel, such that the central longitudinal axis of the auxiliary working channel is not parallel to the central longitudinal axis of the main channel; An endoscope having an endoscope axis sized to extend through the main channel of a sleeve device, such that when the sleeve device is outside the tympanic membrane, the distal portion of the endoscope can be positioned through the tympanic membrane and enter the middle ear to visualize the circular window niche of the cochlea. and An otological syringe device includes: a syringe containing a therapeutic gel formulation comprising an anti-inflammatory agent; and a syringe shaft connected to the syringe, and slidable through an auxiliary working channel of the sleeve device when the endoscope shaft is positioned within the main channel of the sleeve device, wherein a distal tip of the syringe shaft is positioned through the tympanic membrane and is movable distal to a distal portion of the endoscope, such that the distal tip of the syringe shaft can advance into a circular window niche to deliver the therapeutic gel formulation into the circular window niche, while the distal portion of the endoscope is proximally spaced from the distal tip of the syringe shaft to provide visualization of the syringe shaft. The sleeve device is pressed against the outside of the endoscope to fix the sleeve device to the endoscope when the endoscope axis is positioned using the main channel. The syringe shaft includes a first curved portion and a second curved portion, the second curved portion being curved in the opposite direction to the first curved portion, and the first curved portion and the second curved portion having shape memory.

15. The system according to claim 14, wherein, The sleeve device includes an annular interface member that releasably secures the sleeve device to the outside of the endoscope.

16. The system according to claim 14, wherein, The distal tip of the syringe shaft is movable relative to the sleeve device and the distal portion of the endoscope.

17. The system according to claim 14, wherein, The auxiliary working channel of the sleeve device is laterally separated from the main channel through the middle wall portion of the sleeve device.

18. The system according to claim 14, wherein, The therapeutic gel formulation including the anti-inflammatory agent comprises a first functional component and a second functional component, the first functional component and the second functional component being mixed within the syringe to produce a gel crosslinking reaction.

Images