Devices, systems, and methods for treating ear disorders

Abstract

The systems and methods can be employed for transtympanic access to the middle ear for delivery of therapeutic formulations or implant devices to target locations under direct visualization. The systems and methods can also be used to improve access and visualization for various otologic surgical procedures, such as, but not limited to, cholesteatoma removal, tympanic membrane repair, and ossicular chain repair.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 965,481, filed January 24, 2020, U.S. Provisional Patent Application No. 63 / 024,183, filed May 13, 2020 (which are incorporated by reference herein in their entirety), U.S. Provisional Patent Application No. 63 / 040,495, filed June 17, 2020 (which are incorporated by reference herein in their entirety), U.S. Provisional Patent Application No. 63 / 051,568, filed July 14, 2020 (which are incorporated by reference herein in their entirety), U.S. Provisional Patent Application No. 63 / 077,448, filed September 11, 2020 (which are incorporated by reference herein in their entirety). This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 078,141, filed September 14, 2020 (which is incorporated by reference herein in its entirety), U.S. Provisional Patent Application No. 63 / 080,510, filed September 18, 2020 (which is incorporated by reference herein in its entirety), U.S. Provisional Patent Application No. 63 / 081,015, filed September 21, 2020 (which is incorporated by reference herein in its entirety), and U.S. Provisional Patent Application No. 63 / 082,996, filed September 24, 2020 (which is incorporated by reference herein in its entirety).

[0002] This document relates to devices, systems, methods, and materials for treating ear disorders, including but not limited to hearing loss. In certain examples, the systems and methods include transtympanic access to the middle and / or inner ear for targeted delivery of implant devices or therapeutic compounds under direct visualization. [Background technology]

[0003] The human ear is subject to a variety of disorders including, but not limited to, hearing loss, tinnitus, balance disorders including dizziness, Meniere's disease, vestibular neuritis, vestibular schwannoma, otitis interna, otosclerosis, ossicular chain luxation, cholesteatoma, outer ear infection, middle ear infection, schwannoma, and tympanic membrane perforation, to name a few.

[0004] In certain instances, conductive hearing loss (CHL) involves the loss of the normal mechanical pathway for sound to reach the hair cells in the cochlea due to, for example, malformations, fluid accumulation in the middle ear, destruction of the eardrum, the presence of a tumor, and / or damage to the ossicles. Sensorineural hearing loss (SNHL) is due to the absence of hair cells in the cochlea, damage to hair cells in the cochlea, or damage to the auditory nerve. SNHL is typically associated with exposure to loud noise, head trauma, aging, infection, Meniere's disease, tumors, ototoxicity, genetic disorders such as Usher syndrome, etc. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] U.S. Patent No. 9,040,701 Summary of the Invention [Problem to be solved by the invention]

[0006] This document describes devices, systems, and methods for minimally invasive access to the middle ear for the purpose of delivering treatments for inner ear and / or middle ear diseases. For example, this document describes devices, systems, and methods for transtympanic membrane access to achieve minimally invasive delivery of a therapeutic compound or an implant device (capable of delivering a therapeutic compound). In some implementations, the therapeutic compound or implant device is delivered under direct visualization to the round window pit and adjacent to the round window membrane of the cochlea. In specific implementations, the active agent of the therapeutic compound and / or implant device can passively migrate by diffusing across the round window membrane into the perilymph (inside the cochlea) according to a concentration gradient.

[0007] In certain embodiments, the therapeutic compound or implant device is delivered to other targeted regions of the middle ear and / or inner ear, such as, but not limited to, the oval window. In specific embodiments, the therapeutic compound or implant device may be placed directly into the inner ear (perilymph) by injection, with or without a microneedle, across the oval window, across the round window, or into other parts of the cochlea, or through a cochleostomy.

[0008] The devices, systems, materials, compounds, compositions, articles, and methods described herein can be used to treat a variety of disorders of the middle and / or inner ear, including, but not limited to, hearing loss, tinnitus, balance disorders including dizziness, Meniere's disease, vestibular neuritis, vestibular schwannoma, labyrinthitis, otosclerosis, ossicular chain luxation, cholesteatoma, middle ear infection, perilymphatic fistula, and tympanic membrane perforation, to name a few. [Means for solving the problem]

[0009] In one aspect, the disclosure is directed to a system for delivering a therapeutic compound or implant adjacent to a patient's cochlea. The system may include: (i) first and second tympanic membrane port devices configured to be removably implanted at spaced locations in a patient's tympanic membrane, the first tympanic membrane port device defining a first lumen and the second tympanic membrane port device defining a second lumen; (ii) an endoscope slidable through the first lumen of the first tympanic membrane port device while the first tympanic membrane port device is implanted in the tympanic membrane so that a distal end portion of the endoscope is positionable in the middle ear to visualize a target region of the middle or inner ear; and (iii) an instrument slidable through the second lumen of the second tympanic membrane port device while the second tympanic membrane port device is implanted in the tympanic membrane so that a distal tip portion of the endoscope is advanceable to the target region, the instrument configured to deliver a therapeutic compound or implant to the target region while a distal end portion of the endoscope in the middle ear is spaced from the instrument to provide visualization of the instrument.

[0010] Such a system for delivering a therapeutic compound or implant adjacent to a patient's cochlea may optionally include one or more of the following features. The system may also include a tympanic membrane port insert configured to removably implant the first and second tympanic membrane port devices into the tympanic membrane. The tympanic membrane port insert may include an elongate delivery sheath, a pusher catheter, and a trocar needle. In some embodiments, the pusher catheter is slidably disposed within a lumen defined by the delivery sheath. The trocar needle may be slidably disposed within a lumen defined by the pusher catheter. The outer diameter of the trocar needle may be smaller than the inner diameter of the first lumen of the first tympanic membrane port device and the inner diameter of the second lumen of the second tympanic membrane port device. The outer diameter of the pusher catheter may be larger than the inner diameter of the first lumen of the first tympanic membrane port device and the inner diameter of the second lumen of the second tympanic membrane port device. In some embodiments, the distal tip portion of the injection instrument includes a single curve. In some embodiments, the distal tip portion of the injection instrument includes a first curved portion and a second curved portion. The first curved portion and the second curved portion may be in the same plane or may be curved in opposite directions. The system may include a membrane modification instrument slidable through a second lumen of the second tympanic membrane port device while the second tympanic membrane port device is implanted in the tympanic membrane, such that the distal tip portion of the membrane modification instrument is advanceable to the round window region. The membrane modification instrument may be configured to rupture the pseudomembrane at the round window pit while the distal tip portion of the endoscope in the middle ear is spaced from the membrane modification instrument to provide visualization of the membrane modification instrument.

[0011] In another aspect, this disclosure is directed to a system for delivering a therapeutic compound to a target location in a patient's middle or inner ear, the system including: (a) an endoscope including an endoscopic shaft with a distal tip portion sized to be positioned within the middle ear; (b) a sleeve device defining (i) a first lumen configured to slidably receive the endoscopic shaft and (ii) a second lumen; (c) a proximal actuator and an injection device including an injection shaft with a distal tip portion defining a distal delivery port, the injection shaft sized to be slidably received in the second lumen of the sleeve device, the distal tip portion of the injection shaft being longitudinally adjustable from a straight to a curved configuration to orient the distal delivery port at the target location in the middle or inner ear; and (d) a therapeutic compound source in fluid communication with the injection device such that the distal delivery port is configured to deliver the therapeutic compound to the target location while the distal tip portion of the injection device is positioned in the curved configuration.

[0012] Such systems for delivering a therapeutic compound to a target location in a patient's middle or inner ear may optionally include one or more of the following features: The distal tip portion of the injection device may have shape memory to obtain a curved shape. The distal tip portion of the injection device may be selectively adjustable to the curved shape by manipulating one or more control members slidably coupled within a lumen defined by the distal tip portion. The system may also include a first tympanic membrane port device configured to be removably implanted in the patient's tympanic membrane. The first tympanic membrane port device may define a first lumen, and the sleeve device may be configured to pass through the first lumen. In certain embodiments, the sleeve device is configured to pass through the first lumen while the endoscope is in the first lumen and while the injection device is in the second lumen.

[0013] In another aspect, this disclosure is directed to a system for delivering an implant device to a target location in a patient's middle or inner ear. The system may include an endoscope including an endoscopic shaft with a distal tip portion sized to be positioned in the middle ear, a sleeve device defining (i) a first lumen configured to slidably receive the endoscopic shaft and (ii) a second lumen, a proximal actuator, and an implant delivery device including a shaft with a distal tip portion configured to releasably couple with the implant device. The shaft may be sized to be slidably received in the second lumen of the sleeve device. The distal tip portion of the implant delivery device may be longitudinally adjustable from a straight to a curved shape to orient the distal tip portion at the target location in the middle or inner ear.

[0014] Such systems for delivering an implant device to a target location in a patient's middle or inner ear may optionally include one or more of the following features: The system may also include an implant device. The implant device may be solid or semi-solid with one or more therapeutic agents dispersed therein. The implant device may consist of a solid drug matrix surrounded by a drug-permeable material and a drug-impermeable material. The implant device may consist of a metallic or polymeric core to which a drug-eluting coating is applied. The implant device may include an array of microneedles that act as permeation enhancers.

[0015] In another aspect, the present disclosure is directed to a method of treating an ear disease in a patient. The method may include advancing a trocar needle carrying a first tympanic membrane port device into the patient's outer ear, creating a first puncture opening in the patient's tympanic membrane with a distal tip portion of the trocar needle while the trocar needle carries the first tympanic membrane port device, advancing the distal tip portion of the trocar needle through the puncture opening to implant the first tympanic membrane port device into the tympanic membrane, the first tympanic membrane port device defining a first lumen therethrough, advancing an injection instrument into the patient's outer ear and the first lumen until a distal tip of the injection instrument is adjacent a target location in the patient's middle or inner ear, and delivering a therapeutic compound or an implant device at the target location via the injection instrument.

[0016] Such methods of treating an ear condition in a patient may optionally include one or more of the following features: In certain embodiments, the steps of advancing the injection instrument and delivering the therapeutic formulation or implant device are each performed while an endoscope provides directed visualization of the target location and the injection instrument in proximity to the target location.

[0017] In another aspect, the disclosure is directed to an ear implant device sized and shaped to anchor to a portion of the cochlea and having a refillable reservoir containing a therapeutic formulation for sustained release into the round window pit of the cochlea.

[0018] Such an auris implant device may optionally include one or more of the following features: The implant device may be solid. The implant device may be semi-solid. The implant device may consist of a solid drug matrix surrounded by a drug-permeable material and a drug-impermeable material. The implant device may consist of a metal or polymeric core to which a drug-eluting coating is applied. The implant device may include an array of microneedles that act as permeation enhancers.

[0019] In another aspect, this disclosure is directed to a system for delivering an implant device to a patient's round window pit. The system may include an endoscope including an endoscopic shaft with a distal tip portion sized to be positioned in the patient's middle ear, an implant device having a container containing a therapeutic formulation for sustained release into the round window pit, and an implant delivery device including a proximal actuator and a shaft with a distal tip portion configured to releasably couple with the implant device. The distal tip portion of the implant delivery device may be longitudinally adjustable from a straight to a curved shape to orient the distal tip portion in the round window pit.

[0020] Some or all of the embodiments described herein may provide one or more of the following features. First, the systems and methods for treating hearing loss and all other ear disorders described herein may include specialized techniques and instruments that can be used to access the middle ear and / or inner ear and to precisely deliver therapeutic compounds to target locations. The systems and methods for treating hearing loss and all other ear disorders described herein may also include specialized techniques and instruments that can be used to access the middle ear and / or inner ear and to precisely place solid implants or continuous delivery systems over or across the round window membrane or into other parts of the cochlea through a cochleostomy. The systems and methods for treating hearing loss and all other ear disorders described herein may also include specialized techniques and instruments that can be used to precisely deliver therapeutic compounds and / or implant devices to other parts of the middle ear cavity.

[0021] Second, the systems and methods for treating hearing loss described herein deliver therapeutic compounds and / or implant devices to the middle and / or inner ear under direct visualization. The use of such direct visualization advantageously allows for visual confirmation of proper placement of the therapeutic compound and / or implant device with a high level of accuracy. Direct visualization also provides additional benefits, such as the ability to visually confirm whether there are any obstructions that may prevent proper delivery of the therapeutic compound and / or implant device. For example, in some cases, the round window is covered by a pseudomembrane, which can be modified or displaced to allow improved access to the round window pit. Using the improved instruments described herein, the presence of the pseudomembrane can be visually confirmed and then physically modified or displaced to allow improved, direct access to the round window pit. Additionally, after the therapeutic compound and / or implant device has been administered, direct visualization can be used to confirm that the therapeutic compound and / or implant device is retained in the desired position and manner.

[0022] Third, the systems and methods for treating hearing loss and other ear disorders described herein enable direct access to the middle ear cavity through the tympanic membrane using a less suturing and less invasive approach. In some implementations, such access through the tympanic membrane using a tympanic membrane port device can be safer, less invasive, and can be achieved without sealing or repairing the tympanic membrane after removal of the tympanic membrane port device. For example, the small size of the tympanic membrane port device allows the tympanic membrane to heal naturally after removal of the tympanic membrane port device.

[0023] Fourth, the systems and methods for treating hearing loss and other ear disorders described herein facilitate treatment in a minimally invasive manner. Such minimally invasive techniques may tend to reduce recovery time, patient discomfort, and treatment costs. Furthermore, the methods described herein can be performed using local anesthesia rather than requiring general anesthesia. Thus, treatment costs, patient risks, and recovery times are further advantageously reduced.

[0024] Fifth, the systems described herein can also be used for diagnostic purposes. Such use can aid in treatment planning, alter the site of care, and potentially improve patient outcomes.

[0025] The 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 be apparent from the description and drawings, and from the claims. [Brief explanation of the drawings]

[0026] [Figure 1] 1 is a schematic diagram of a medical procedure for treating hearing loss, according to an embodiment. [Figure 2] 2 is a perspective view of a therapeutic gel substance positioned within the cochlea and delivered through the round window of the cochlea according to the treatment procedure of FIG. 1. FIG. [Figure 3] FIG. 1 is a perspective view of an example tympanic membrane port device mounted on a delivery trocar, according to an embodiment. [Figure 4] FIG. 4 is a perspective view of the tympanic membrane port device of FIG. [Figure 5] FIG. 4 is a perspective view of an example endoscopic instrument with a distal viewing tip configured to be advanced through the tympanic membrane port device of FIG. 3 and into the middle ear. [Figure 6] FIG. 4 is a perspective view of an example membrane modification instrument configured to be advanced into the middle ear through the tympanic membrane port device of FIG. 3. [Figure 7]FIG. 4 is a perspective view of an example therapeutic agent injection tool configured to be advanced into the middle ear through the tympanic membrane port device of FIG. 3. [Figure 8] FIG. 1 illustrates a patient in position for a medical treatment procedure to treat hearing loss and other ear disorders as described herein. [Figure 9] 1 illustrates the advancement of a sheath into a patient's outer ear toward the patient's tympanic membrane. [Figure 10] 1 illustrates a puncture in a patient's tympanic membrane and placement of a tympanic membrane port device on the patient's tympanic membrane. [Figure 11] FIG. 1 is a diagram of two tympanic membrane port devices positioned on a patient's tympanic membrane. [Figure 12] FIG. 16 is a perspective view of a sheath for delivering a tympanic membrane port device. [Figure 13] FIG. 13 is a perspective view of the sheath of FIG. 12 with a tympanic membrane port device and a delivery trocar extending distally from the sheath. [Figure 14] FIG. 14 is a perspective view of the device of FIG. 13 with the needle of the delivery trocar retracted proximally. [Figure 15] FIG. 14 is a perspective view of the tympanic membrane port device of FIG. 13 separated from the sheath and delivery trocar. [Figure 16] FIG. 1 is a diagram of the right tympanic membrane with overlaid lines and markings indicating the coordinates of locations around the tympanic annulus that surrounds the tympanic membrane. [Figure 17] 1A-1C are diagrams of an example tympanic membrane port device with an anchoring portion. [Figure 18] FIG. 18 is a diagram of the tympanic membrane and annulus with two tympanic membrane port devices of FIG. 17. [Figure 19] FIG. 1 is a diagram of the tympanic membrane and annulus with an example dual tympanic membrane port device. [Figure 20] FIG. 10 is a diagram of the tympanic membrane and annulus with another example dual tympanic membrane port device. [Figure 21] FIG. 1 is a diagram of the tympanic membrane and annulus with an example triple tympanic port device. [Figure 22] 10A-10C are diagrams of another example injection device extending through an example tympanic membrane port device. [Figure 23] 23A and 23B are cross-sectional views of examples of extendable infusion tubes of the infusion device of FIG. 22. [Figure 24] FIG. 1 is a diagram of an example therapeutic agent delivery device coupled to an example infusion device. [Figure 25] FIG. 10 illustrates an example infusion device extending through an example tympanic membrane port device in a first configuration. [Figure 26] FIG. 26 is a view of the example injection device of FIG. 25 extending through the example tympanic membrane port device in a second configuration. [Figure 27] FIG. 26 is a view of the example injection device of FIG. 25 extending through the example tympanic membrane port device in a third configuration. [Figure 28] 11A and 11B illustrate two tympanic membrane port devices at a patient's tympanic membrane, an example endoscopic device extending through a first of the tympanic membrane port devices, and an example injection device extending through a second of the tympanic membrane port devices. [Figure 29] FIG. 29 is a diagram of the injection device of FIG. 28 extended and oriented in preparation for injecting a therapeutic agent into the round window of a patient's cochlea. [Figure 30] FIG. 29 is a diagram of the infusion device of FIG. 28 delivering a dose of therapeutic agent to the round window of a patient's cochlea. [Figure 31] FIG. 1 is a diagram of an example light energy delivery device projecting light energy onto a therapeutic agent to photocure the therapeutic agent as a gel. [Figure 32] 1A and 1B are diagrams of an example otic instrument with an optional removable sleeve device defining a functional passageway connected to the shaft of the instrument. [Figure 33] 33 is a transverse cross-sectional view of the example removable sleeve device of FIG. 32. [Figure 34] 33 is a cross-sectional view of another example of the removable sleeve device of FIG. 32. [Figure 35] 33 is a cross-sectional view of another example of the removable sleeve device of FIG. 32. [Figure 36]33 is a diagram of an example injection system, implant refill system, or example extraction system for use with the removable sleeve device of FIG. 32. [Figure 37] 37 is a diagram of an example distal tip portion of the example injection system, implant refill system, or example extraction system of FIG. 36. [Figure 38] 37A-37C are views of various example distal tip portions of needles or cannulas of the example injection system, implant refill system, or example extraction system of FIG. 36. [Figure 39] FIG. 37 is a diagram of an example microneedle array of the example injection system, implant refill system, or needle or cannula of the example extraction system of FIG. 36. [Figure 40] FIG. 33 is a diagram of an example implant delivery system for use with the removable sleeve device of FIG. 32. DETAILED DESCRIPTION OF THE INVENTION

[0027] Like numbers in the various drawings indicate like elements.

[0028] 1-2 , specific embodiments of systems and methods for treating a patient 10 may include an improved set of medical instruments for delivering a therapeutic formulation 100 (or an implantable device releasing such a therapeutic formulation) containing a therapeutic agent or active ingredient to a target site in the patient 10, e.g., under direct endoscopic visualization. As described herein, in some cases, the therapeutic formulation 100 is a liquid or gel, and the target site is the round window pit of the cochlea 50. However, the inventive concepts disclosed herein are not so limited. That is, while the inventive concepts are described primarily in the context of an example of delivery of a liquid or gel therapeutic formulation to the round window pit of the cochlea 50, it should be understood that the inventive aspects disclosed herein are broader than those specific examples. For example, in some cases, the target site is other locations in the middle and / or inner ear region, such as, but not limited to, the oval window, other portions of the cochlea through a cochleostomy, or other regions of the middle and / or inner ear. Additionally, in some cases, implantable devices (also referred to herein as "implant devices," "solid implants," or "implants") are delivered using the devices, systems, and methods described herein. Such implants can release therapeutic agents over a period of time. Thus, the devices, systems, materials, compounds, compositions, articles, and methods described herein are applicable to the delivery of therapeutic formulations and / or implants to any / all regions of the middle and / or inner ear.

[0029] The devices, systems, and methods described herein can be used to treat and / or prevent a variety of conditions, including hearing loss including, but not limited to, 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 disease, cholesteatoma, and the like.

[0030] Although the devices, systems, materials, compounds, compositions, articles, and methods described herein are described herein primarily in the context of treating and / or preventing hearing loss, it should be understood that the devices, systems, materials, compounds, compositions, articles, and methods can be used to treat and / or prevent any other disease of the middle and / or inner ear, including, but not limited to, tinnitus, balance disorders including dizziness, Meniere's disease, vestibular neuritis, vestibular schwannoma, labyrinthitis, otosclerosis, ossicular chain luxation, cholesteatoma, middle ear infection, and tympanic membrane perforation, to name a few.

[0031] This disclosure describes treatment methods and devices for treating a patient 10 using a minimally invasive approach. As depicted in FIG. 1 , a clinician 1 approaches the cochlea 50 through the ear canal 20 of the patient 10 using various instruments (here collectively represented by the generic instrument 110), as described further below. The instrument 110 is advanced through the tympanic membrane (TM) 30 via one or more temporarily implanted tympanic membrane port devices 200. A distal end portion of the instrument 110 is thereby advanced into the middle ear 40 toward the round window 52 of the cochlea 50.

[0032] As described in more detail below, the system's instruments can be configured to achieve targeted delivery of the formulation or implant 100 into the round window pit 52 and adjacent to the round window membrane of the cochlea 50. The active ingredient of the formulation or implant 100 then passively moves by diffusion across the membrane of the round window 52 into the perilymph (within the cochlea 50) according to a concentration gradient. In certain embodiments, the formulation or implant 100 delivered adjacent to the round window membrane of the cochlea 50 can then reside adjacent to or within the pit of the round window 52 as a semi-solid gel substance. As a gel substance, the delivery of the formulation or implant 100 will remain at the target site in the cochlea 50, allowing the formulation or implant 100 to gradually release its active ingredient over an extended period of time, such as over days, weeks, or months.

[0033] After delivery of the formulation or implant 100, the instrument 110 and one or more TM port devices 200 can be removed from the patient 10. The TM port device 200 can be sized and shaped to allow the opening in the TM 30 (through which the TM port device 200 was positioned) to heal naturally (without suturing). The formulation or implant 100 (e.g., in the form of a gel) will remain at the target site in the cochlea 50 to provide a long-lasting therapeutic effect through controlled and sustained release of the active ingredient into the body of the patient 10.

[0034] Sustained release may encompass the release of an effective amount of the active ingredient of the formulation or implant 100 over an extended period of time. Sustained release may encompass first order release of the active ingredient, zero order release of the active ingredient, or other kinetics such as intermediate to zero order and first order, or a combination thereof. Sustained release may also encompass the controlled release of the active ingredient of the formulation or implant 100 via passive molecular diffusion driven by a concentration gradient across a membrane or porous structure.

[0035] The treatment procedure for delivering the formulation or implant 100 to the cochlea 50 of the patient 10 may be repeated periodically as required for a particular patient's treatment. For example, in some cases, delivery of the formulation or implant 100 may be administered about every 3 months to about every 24 months, each time using a new TM port device 200 and delivery apparatus as described herein. In particular cases, an evaluation of the patient 10 may be performed to determine whether or when to administer more formulation or implant 100. In some cases, a treatment procedure such as magnetic resonance imaging (MRI) (or other type of treatment procedure) may be performed to help make such an evaluation.

[0036] 3-7, an example system (or kit) of devices and instruments that can be used to perform treatment procedures to treat hearing loss and other ear disorders as described herein may include, but is not limited to, one or more of the following: (i) a TM port insert 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) a forceps 400 (or other type of tissue manipulation device, as described further below) sized to fit through the TM port device 200; and (v) an injection instrument 800 sized to fit through the TM port device 200, and (optionally) having a steerable distal tip.

[0037] The endoscope 300, forceps 400, and injection instrument 800 are configured to access the middle ear 40 through the TM port device 200 while each TM port device 200 is temporarily implanted in the TM 30 of the patient 10. That is, at least a distal end portion of each of the endoscope 300, forceps 400, and injection instrument 800 is configured to slidably pass through the lumen 202 defined by the TM port device 200 while the TM port device 200 is removably implanted in the TM 30. If the endoscope 300, injection instrument 800, or any other instrument is of a different diameter or outer shape, the TM port device 200 may be of a different size or shape to accommodate it accordingly. In certain embodiments, as described further below, the endoscope 300 (while its distal end portion is positioned in the middle ear 40) is used by the clinician 1 to obtain direct visualization as the clinician 1 manipulates forceps 400 or other instruments, such as an injection instrument 800, in the middle ear 40 to perform treatments for hearing loss and other ear disorders, as described herein. The injection instrument 800 may be adapted to deliver therapeutic formulations and / or implants.

[0038] In use, a proximal end portion of each of the depicted instruments remains external to the patient 10 and is operable / controllable by the clinician 1. Each of the instruments, the TM port device 200, and the preparation or implant 100 are further described below.

[0039] 8, a patient 10 is depicted in example positions and orientations suitable for undergoing treatment procedures to treat hearing loss and other ear disorders as described herein. In some cases, the treatment procedures may be performed with the patient 10 in a fully supine position (as shown) or reclining in a chair.

[0040] The patient's 10 head may be rotated between about 30 degrees and about 45 degrees away from the clinician 1 (toward the patient's 10 opposite ear). The patient's 10 chin may be slightly lifted and / or the exterior of the patient's 10 ear may be pulled upward and backward to adjust the opening and angle of the ear canal so that the patient's round window 52 is oriented generally upward (e.g., away from the ground) so that dispensing of the formulation or implant 100 from the delivery device allows the formulation or implant 100 to pool in the round window 52 and not flow toward the Eustachian tube or ossicular chain.

[0041] In some implementations, the patient 10 remains awake during the procedure. That is, the procedure can be performed using local anesthesia rather than general anesthesia. For example, in some cases, an agent such as phenol or lidocaine can be applied to the TM 30 as a local anesthetic to facilitate the procedure. In some cases, the patient 10 can be given general anesthesia for the procedure.

[0042] 9 , after preparing the patient 10 for the procedure, the TM port insert 220 may be advanced into the ear canal 20 toward the TM 30 as part of the procedure to temporarily implant the TM port device 200 in the TM 30. In some cases, an endoscope (not shown) is used in the ear canal 20 to provide direct visualization of the TM port insert 220 as the TM port insert 220 is advanced and used to insert the TM port device 200 in the TM 30. In some cases, a surgical microscope or other magnifying instrument is used to provide direct visualization of the TM port insert 220 as the TM port insert 220 is advanced and used to temporarily implant the TM port device 200 in the TM 30.

[0043] 12-15, an example TM port inserter 220 includes an elongate delivery sheath 222, a pushing catheter 224, and a trocar needle 226. The pushing catheter 224 is slidably disposed within a lumen defined by the delivery sheath 222. The trocar needle 226 is slidably disposed within a lumen defined by the pushing catheter 224. In a specific embodiment, the pushing catheter 224 and the trocar needle 226 are combined together as a single device.

[0044] When the TM port device 200 is operably attached to the TM port insert 220 (e.g., FIG. 13 ), the TM port device 200 is releasably coupled to the trocar needle 226, abuts the distal end of the pusher catheter 224, and is slidably positionable within the lumen of the delivery sheath 222. That is, at least the distal end portion of the trocar needle 226 is slidably positioned within the lumen 202 of the TM port device 200. In certain embodiments, a loose fit is used between the outer diameter of the distal end portion of the trocar needle 226 and the inner diameter of the lumen 202 of the TM port device 200. In a specific embodiment, a slight interference fit is used between the outer diameter of the distal end portion of the trocar needle 226 and the inner diameter of the lumen 202 of the TM port device 200.

[0045] While the TM port device 200 is coupled to the trocar needle 226, the distal end face of the pusher catheter 224 abuts (or can abut) against the proximal end face of the TM port device 200. Thus, the pusher catheter 224 can apply a distally directed force to the TM port device 200 during or to disconnect the TM port device 200 from the trocar needle 226 (and from the TM port insert 220 as a whole). Simply put, the pusher catheter 224 can be used to push the TM port device 200 distally off the trocar needle 226. Or, stated another way, the pusher catheter 224 can counteract a proximally directed force from the TM port device 200 when the trocar needle 226 is pulled proximally from the lumen 202 of the TM port device 200.

[0046] The TM port device 200 is slidably disposed within a lumen defined by the delivery sheath 222. That is, the TM port device 200 can be removably housed within the lumen of the delivery sheath 222 (as in FIG. 12 , where the TM port device 200 is positioned inside the delivery sheath 222 and therefore not visible). This arrangement can be used, for example, during advancement of the TM port insert 220, fitted with the TM port device 200, into the ear canal 20, as depicted in FIG. 9 .

[0047] The example TM port device 200 comprises three joined, adjacent sections: (i) a distal end section 204, (ii) an intermediate section 206, and (iii) a proximal end section 208. A lumen 202 extends through the center of each of sections 204 / 206 / 208. In certain embodiments, lumen 202 has a diameter ranging, without limitation, from 0.4 mm to 0.6 mm, from 0.5 mm to 0.75 mm, or from 0.5 mm to 1.0 mm.

[0048] The inner diameter or lumen of the proximal end portion 208 may be tapered to have a larger diameter at the proximal end to create a funnel-like shape to facilitate alignment of instruments as they enter the port device.

[0049] The distal end portion 204 may be frustoconical in shape. That is, the distal-most end of the distal end portion 204 has a smaller outer diameter than the proximal-most end of the distal end portion 204. The intermediate portion 206 and the proximal end portion 208 are each cylindrical. The outer diameter of the intermediate portion 206 is smaller than the outer diameter of each of (i) the proximal-most end of the distal end portion 204 and (ii) the proximal-most end of the proximal end portion 208. Thus, the intermediate portion 206 may be considered the "waist region" of the TM port device 200 in this embodiment. The lumen 202, like the distal end portion 204, may be conical, cylindrical, elliptical, pyramidal, or other shape.

[0050] As described further below, the intermediate portion 206 is where the tissue of the TM 30 will be (at least primarily) located while the TM port device 200 is implanted in the TM 30. The relatively smaller outer diameter of the intermediate portion 206 (as compared to the outer diameters of the adjacent portions of the distal end portion 204 and proximal end portion 208) facilitates placement of the TM port device 200 in the TM 30. In certain embodiments, the outer diameter of the intermediate portion 206 ranges, without limitation, from 0.25 mm to 0.75 mm, from 0.25 mm to 1.0 mm, or from 0.5 mm to 1.25 mm. The longitudinal length of the intermediate portion 206 can range, without limitation, from 0.1 mm to 0.3 mm, from 0.1 mm to 0.5 mm, or from 0.2 mm to 0.6 mm. The outer diameter and length of the intermediate portion 206 are sufficient to accommodate the thickness of the TM 30 while preventing buckling, tearing, or other forces from being inadvertently applied to the TM 30 during insertion of the TM port device 200. In some embodiments, no waisted region is included, and the friction fit between the distal section and the TM is sufficient to hold the port device in the TM throughout the procedure while reducing the forces the TM is exposed to during port insertion or removal.

[0051] In some embodiments, the TM port device 200 can be implanted into the TM 30 without the use of a trocar needle. Instead, an incision in the TM 30 can be first made 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.

[0052] While the TM port device 200 is implanted (or attached, coupled, engaged, etc.) to the TM 30, the TM port device 200 acts as a grommet, a stress relief member to prevent tearing of the TM 30, a middle ear access port, an instrument insertion tunnel, a functional passageway, etc.

[0053] The TM port device 200 is configured and sized so that its removal from the TM 30 does not require the use of sutures to seal the incision or fenestration formed in the TM 30 during insertion of the TM port device 200. Generally, the self-sealing fenestration through the TM 30 is about 2.5 mm or less in length, preferably between about 0.5 mm and 1.5 mm. While the tools and methods described herein provide the advantage of suture-free access to the middle and / or inner ear, this does not preclude a surgeon from applying one or more closure techniques in removing the TM port device 200. That is, if the clinician 1 so desires, one or more techniques for closure of the fenestration in the TM 30 may be implemented.

[0054] The TM port device 200 can be formed from a material that has the rigidity and strength to insert into and remove from the TM 30, while also withstanding stresses that may occur during manipulation of surgical instruments inserted through the TM port device 200. In some embodiments, at least a portion of the TM port device 200 is formed from a surgical metal such as stainless steel, titanium, platinum, nitinol, and / or a plastic such as polyimide, PEEK, fluoropolymer, or silicone. In some embodiments, the inserted portion of the TM port device 200 can be formed from polyimide (or other rigid or semi-rigid polymer) and have a maximum outer diameter of about 20 gauge (0.8 mm) or less. One or more portions of the TM port device 200 can be coated with or formed from a resilient, conformable material. For example, the retention feature 102 can be coated with or formed by an overmolding of a material such as silicone or polyurethane.

[0055] 9, in preparation for implanting the TM port device 200 into the TM 30, the TM port insert 220, with the TM port device 200 integrally attached, is advanced toward the TM 30 in the ear canal 20. During advancement, the TM port insert 220 may be configured as in FIG. 12, with the pusher catheter 224, trocar needle 226, and TM port device 200 all within the lumen of the delivery sheath 222.

[0056] 10 , when the delivery sheath 222 is advanced within the ear canal 20 to the extent that the distal end of the delivery sheath 222 is adjacent the TM 30, the pusher catheter 224, trocar needle 226, and TM port device 200 may be extended distally from within the delivery sheath 222 (as also depicted in FIG. 13 ). The distal tip portion of the trocar needle 226 may be configured to puncture the TM 30 due to its beveled, sharp tip configured to puncture the TM 30. As the pusher catheter 224 (and, optionally, the trocar needle 226) is extended further distally, the distal end portion 204 ( FIG. 15 ) of the TM port device 200 enters and enlarges (dilates) the puncture in the TM 30 initially created by the trocar needle 226. Advancement even further will position the intermediate portion 206 of the TM port device 200 in constrained engagement with the TM 30. Next, as depicted in FIG. 15, the TM port insert 220 can be retracted from the TM port device 200, leaving the TM port device 200 releasably coupled with the TM 30.

[0057] 11 , one or more TM port devices 200 may be temporarily / removably implanted in the TM 30. During implantation, a proximal end portion 208 of the TM port device 200 is positioned in the ear canal 20, a distal end portion 204 of the TM port device 200 is positioned in the middle ear 40, and an intermediate portion 206 of the TM port device 200 receives tissue of the TM 30. During implantation, a lumen 202 of the TM port device 200 defines an open passage between the ear canal 20 and the middle ear 40. In certain embodiments, the passage of the TM port device 200 between the ear canal and the middle ear can house a friction element, valve, or other element to regulate the movement of instruments, gases, or liquids through the passage of the TM port device 200.

[0058] As depicted, in one embodiment, two TM port devices 200 are temporarily implanted in the TM 30. In such a case, the two TM port devices 200 may be spaced laterally from one another (e.g., laterally relative to an axis defined by the passageway of the TM port devices 200) while implanted in the TM 30. In one embodiment, the two TM port devices 200 are spaced laterally from one another by a distance ranging from 0.5 mm to 8 mm while implanted in the TM 30.

[0059] 16 shows the right TM 30 with superimposed lines and markings indicating the coordinates of the location around the tympanic annulus 32 that surrounds the tympanic membrane 30. The location at the tympanic annulus 32 can be identified using a clock face likened to the malleus being positioned at 12 o'clock.

[0060] The TM 30 is a thin, cone-shaped membrane that separates the outer ear from the middle ear. The tympanic annulus 32 is a thicker ring of fibrocartilage that circumferentially surrounds the TM 30. Thus, the tympanic annulus 32 provides a strong, stable tissue to anchor the TM port device.

[0061] 17 shows another example TM port device 1400. The TM port device 1400 includes a laterally extending tether 1420 attached to a cannula 1410. The cannula 1410 defines a port 1412 that serves as a passageway for the instruments described herein. Such a laterally extending tether 1420 may be optionally included in any of the TM port devices described herein.

[0062] As described further below, the cannula 1410 can be anchored to the TM 30 (implanted during the procedure and then removed) while the anchoring portion 1420 is positioned at the annulus 32 (so that the TM 30 can be passed through the port 1412 during the procedure). In this manner, the strong annulus 32 serves as a stable base for anchoring the port device 1400. Thus, the anchoring portion 1420 transfers stress to the annulus 32 when instruments are used in the port 1412, such that stress on the TM 30 itself is minimized.

[0063] The anchoring portion 1420 has a sharp, pointed tip 1422 that can pierce through the tympanic annulus 32 when the tympanic port device 1400 is implanted in the TM 30 and the annulus 32. The lateral length of the anchoring portion 1420 can be any desired length. The length of the anchoring portion 1420 will help define the resulting position of the cannula 1410 in the TM 30.

[0064] Although the cannula 1410 is depicted as having a cylindrical outer shape, the cannula 1410 is not limited to such a shape. For example, in some embodiments, the outer shape of the cannula 1410 can be as shown in FIG. 15 (e.g., TM port device 200) and elsewhere herein. In some embodiments, the outer shape of the cannula 1410, or a portion thereof, can be frusto-conical, hourglass-shaped, arcuate, etc. The port 1412 can also have various cross-sectional shapes. For example, in some embodiments, the port 1412 is curved rather than linear as shown.

[0065] 18 shows the tympanic membrane 30 and annulus 32 with two tympanic membrane port devices 1400 implanted. It can be seen that the cannula 1410 is positioned to provide a passageway through the TM 30, while the anchoring portion 1420 extends to and penetrates through the annulus 32. Thus, the annulus 32 provides a strong and stable anchorage for the tympanic membrane port device 1400.

[0066] It is envisioned that the anchoring portion 1420 can be used to attach or puncture another member, such as an elastomeric or hydrogel annulus positioned over the tympanic annulus 32. The elastomeric annulus can be placed on the tympanic membrane so that it collapses deep in the ear canal and expands back into shape around the membrane overlying the annulus. This detachable member can thus obviate the need to directly puncture or attach to the annulus while still allowing for stabilization and anchoring of the port 1412.

[0067] 19 illustrates the tympanic membrane 30 and annulus 32 with an implanted example dual tympanic membrane port device 1500. The dual 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 TM 30 are provided by the dual tympanic membrane port device 1500.

[0068] The tympanic membrane port devices 1510a and 1510b are connected to one another 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 membrane port devices 1510a and 1510b.

[0069] FIG. 20 illustrates the tympanic membrane 30 and tympanic annulus 32 with another example dual tympanic membrane port device 1500 implanted. 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 punctures through the tympanic membrane annulus 32 (e.g., as described above with reference to the anchoring portion 1420 of the tympanic membrane port device 1400 ( FIGS. 17 and 18 )). It should be understood that the anchoring portion 1520 may extend laterally from the dual tympanic membrane port device 1500 in any desired direction. While the depicted dual tympanic membrane port device 1500 includes a single anchoring portion 1520, in some embodiments, two or more anchoring portions 1520 may be attached to the dual tympanic membrane port device 1500. Thus, in some embodiments, the dual tympanic membrane port device 1500 may be anchored in more than one location on the tympanic membrane annulus 32 (in addition to passing through the TM 30 in two locations).

[0070] 21 illustrates a tympanic membrane 30 and annulus 32 with an example triple tympanic membrane port device 1600. The triple 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-1610c defines a port through the TM 30.

[0071] The tympanic membrane port devices 1610a-1610c are interconnected via a connecting member 1612. The connecting 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-1610c. In certain embodiments, one or more anchoring portions (e.g., such as anchoring portion 1520 (FIG. 20)) can be attached to the triple tympanic membrane port device 1600 to facilitate anchoring of the triple tympanic membrane port device 1600 at the tympanic membrane annulus 32.

[0072] In some cases, the third port device may instead be a lens to allow transtympanic viewing of the middle ear through a working microscope. This eliminates the need for an endoscope, freeing the surgeon's hands and allowing visualization with both eyes. This lens may be convex to allow viewing over a wider field of view than is possible with an external microscope alone.

[0073] 22, an example injection tool 800 is shown in greater detail. The injection tool 800 may be adapted to deliver a therapeutic compound or an implant device that delivers a therapeutic compound.

[0074] In the depicted embodiment, the injection device 800 comprises a sheath 802 and an injection tube 820. The injection tube 820 is slidable within a lumen defined by the sheath 802. That is, the injection tube 820 can be selectively extended distally from the distal end of the sheath 802 by the clinician 1 as depicted here. The injection tube 820 can also be selectively retracted proximally into the sheath 802 by the clinician 1 so that it 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 makes up the distal end portion 810 of the injection device 800. The distal end portion 810 terminates at a distal tip 812 that defines a port through which a therapeutic agent or drug is released.

[0075] The portion of the injection tube 820 that makes up the distal end portion 810 of the injection device 800 can have a variety of shapes and form factors. For example, in the depicted example, the exposed injection tube 820 comprises a linear portion 822, a first curved portion 824, and a second curved portion 826. However, curved portions 824 and 826 become linear when the injection tube 820 is constrained within the sheath 802. Alternatively, curved portions 824 and 826 take the form of a lumen in the injection tube 820 if the lumen is not linear.

[0076] The curved portions 824 and 826 can be said to have shape memory, that is, when the clinician 1 extends the curved portions 824 and 826 from the confinement of the sheath 802, the curved portions 824 and 826 return to assume the curved shape as shown.

[0077] In a specific embodiment, the combination of the first curved portion 824 and the second curved portion 826 defines an "S-shape" for the distal end portion 810 of the injection device 800. The S-shape is formed because the first curved portion 824 is curved in the opposite direction compared to the curvature of the second curved portion 826. Stated another way, the center point of the radius of curvature of the first curved portion 824 is on the opposite side of the injection 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 injection tube 820 with the linear portion 822, the first curved portion 824, and the second curved portion 826 is merely one example of the type of shape the injection tube 820 can have. Other shapes are contemplated and are within the scope of the present disclosure (such as, but not limited to, the shapes shown in FIGS. 38-40 as described below).

[0078] It can be assumed that when clinician 1 begins to extend infusion tube 820 distally from the distal end of sheath 802, second curved portion 826 will emerge first. Thus, distal end portion 810 will initially have a single curve (as indicated by second curved portion 826). If clinician 1 continues to extend infusion tube 820 distally from the distal end of sheath 802, eventually first curved portion 824 will begin to emerge. It can be assumed that as first curved portion 824 emerges, the entire distal end portion 810 will be deflected to correspond to the opposite direction of second curved portion 826.

[0079] As the injection tube 820 is extended from the distal end of the sheath 802 to various lengths, the distal tip 812 is moved to various positions due to the shape memory of the first curved portion 824 and the second curved portion 826. Thus, the distal tip 812 is controllably positionable by the clinician 1 by controlling the degree to which the injection tube 820 is extended from the distal end of the sheath 802 and using axial rotation of the instrument 800. In other words, the clinician 1 can steer the distal end portion 810 and the distal tip 812 by specifically controlling the degree to which the injection tube 820 is extended from the distal end of the sheath 802. This functionality can be used by the clinician 1 to precisely position the distal tip 812 at the round window 52 in preparation for injecting a therapeutic agent.

[0080] Distal end portion 810 comprises a first curved portion 824 and a second curved portion 826 that are curved in the same plane but in opposite directions, although in some embodiments, distal end portion 810 may comprise two or more curved portions that lie in different planes.

[0081] In certain embodiments, the shape of the distal end portion 810 can be selectively controlled by the clinician 1 using a control member positioned within a lumen defined in the wall of the infusion tube 820. For example, FIG. 23 shows a cross section (taken along dashed line 23-23 in FIG. 22) of one example of various types of tube configurations from which the infusion tube 820 can be made. For example, it can be seen that tube 820a comprises a first pair of lumens 821a and 821b that are 180° opposite one another. In certain embodiments, such lumens 821a, 821b can accommodate control wires that are anchored, for example, near the distal tip 812. Thus, when the clinician 1 pulls proximally on one of the wires and releases tension on the opposite one of the wires, the distal end portion 810 will deflect in the direction of the pulled wire. In this manner, the clinician 1 can steer the distal end portion 810 as desired.

[0082] Additionally, example tube 820a also includes a second pair of lumens 823a and 823b, which define a plane that is perpendicular to the plane defined by the first pair of lumens 821a and 821b. Again, second pair of lumens 823a and 823b can accommodate control wires, for example, anchored near distal tip 812. Thus, when clinician 1 pulls proximally on one of the wires and releases tension on the opposite one of the wires, distal end portion 810 will deflect in the direction of the pulled wire.

[0083] If all four lumens 821a, 821b and 823a, 823b accommodate such control wires, it may be envisioned that clinician 1 can control the orientation or steer distal end portion 810 to extend in any direction and to have any orientation as desired. Furthermore, this may be true either when distal end portion 810 has a shape memory with one or more curves (e.g., as depicted in FIG. 41 ) or when distal end portion 810 is originally linear.

[0084] While example tube 820a has a particular arrangement of lumens 821a, 821b and 823a, 823b, other example tubes 820b and 820c have other arrangements of lumens. Thus, tubes 820b and 820c, or tubes with any other arrangement of lumens, can also be used in accordance with the concepts described in the context of example tube 820a.

[0085] In some embodiments, lumens in the wall of the infusion tube, such as lumens 821a, 821b and 823a, 823b of tube 820a, can house a control member that is a stiffening element. Such stiffening elements can be used to controllably deflect or steer distal end portion 810. For example, in some embodiments, infusion tube 820 inherently has one or more curves (e.g., first curved portion 824 and second curved portion 826). When a stiffening element (e.g., a strong, bend-resistant linear shaft) is moved distally through the lumen in the wall of infusion tube 820 into the region of the curve, the curve tends to straighten. Conversely, when such a stiffening element is pulled proximally from the region of the curve, the curve is corrected again. In such an approach using a stiffening element in the wall of infusion tube 820, clinician 1 can control the orientation or steer distal end portion 810 to extend in any direction and have any orientation as desired. Conversely, in certain embodiments, the infusion tube 820 may be generally linear, while the reinforcing element may have a preformed curvature (e.g., a biased, laser-cut wire or hypotube, a shape-memory element or wire, or a hypotube made from a material such as Nitinol). Such a reinforcing element may be pushed distally relative to a relatively inflexible access shaft such that the curvature of the reinforcing element imparts a curvature to the distal tip of the infusion tube. It is envisioned that reinforcing elements with different degrees of pre-set curvature may be switched to adjust the curvature while leaving the infusion tube 820 in place, thereby limiting potential obstruction of the TM 30. In other embodiments, the reinforcing element may be a shape-memory element (e.g., Nitinol) that assumes its curvature upon exposure to an elevated temperature, such as the temperature inside the patient. In other embodiments, the elevated temperature may be greater than the temperature inside the patient. In such cases, the elevated temperature may be reached by applying a voltage to the Nitinol element, by exposure to heat generated by a light source, or by other techniques for heating the Nitinol element.

[0086] 24, in certain embodiments, the therapeutic formulation 100 begins to become a gel substance when the two liquid components are mixed together, such as by the example dual syringe 1000. The dual syringe 1000 mixes the two liquid components during injection so that they mix immediately prior to delivery. The gelation reaction time between the two liquid components results in a uniform mixing of the two liquid components to quickly reach a gel consistency consistent with the design of the dual syringe 1000.

[0087] The dual syringe 1000 comprises a first barrel 1010, a second barrel 1020, a dual plunger 1030, a Y-connector 1040, and a static mixer 1050. The outlet of the static mixer 1050 is releasably coupled to an injection device, such as injection device 800.

[0088] The first and second barrel portions 1010 and 1020 contain first and second liquid components, respectively, and keep the first and second liquid components separate from each other while they are in the first and second barrel portions 1010 and 1020. The dual plunger 1030 comprises two plungers (one for each of the first and second barrel portions 1010 and 1020) that are coupled together so that displacement of the two plungers can be synchronized during injection by the clinician 1. The Y-connector 1040 receives the first and second liquid components dispensed from the first and second barrel portions 1010 and 1020 and directs the first and second liquid components to flow into contact with each other at the outlet of the Y-connector 1040. The static mixer 1050 receives the first and second liquid components from the Y-connector 1040 and mixes the first and second liquid components together to create a uniform mixture of the first and second liquid components. The uniform mixture of the first and second liquid components exiting the static mixer 1050 enters the injection apparatus 800, from which it can be delivered adjacent to the cochlea 50 of the patient 10.

[0089] In other embodiments, a single syringe may be used to deliver the therapeutic formulation or implant 100. In such cases, the gelation time of the formulation components of the therapeutic formulation or implant 100 is adjusted so that the formulation components can be mixed near the patient and delivered immediately (before the cross-linking reaction or a significant portion of the cross-linking reaction of the formulation components has occurred) to the cochlea 50 using a standard single syringe attached to an injection device. Furthermore, in some embodiments, photocrosslinking is used (e.g., FIG. 31). Thus, in some embodiments, delivery of the mixed formulation components to the pit of the round window 52 is quickly followed by application of light to the middle ear 40 toward the round window 52 to initiate and / or accelerate cross-linking and create a gel consistency of the therapeutic formulation 100. In some embodiments, the gel consistency is generated upon exposure to heat generated by the patient's own body or by other devices.

[0090] The gel consistency of the therapeutic formulation 100 allows the therapeutic formulation 100 to remain adjacent to the round window membrane of the cochlea 50, facilitating either 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 an extended period of time. Sustained release may encompass first-order release of the active ingredient, zero-order release of the active ingredient, or other kinetics such as intermediate to zero-order and first-order, or a combination thereof. Sustained release may encompass the controlled release of the therapeutic formulation 100 via passive molecular diffusion driven by a concentration gradient across the porous structure.

[0091] The composition of the therapeutic formulation 100 can be a mixture. The composition can be a solution, suspension, emulsion, liquid, mist, powder, paste, aqueous, non-aqueous, or any combination of such forms and / or components. A fluid is any composition that can flow. Thus, fluid encompasses compositions that are in the form of semi-solids, pastes, solutions, aqueous mixtures, gels, lotions, creams, and other such compositions.

[0092] 25-27 show another example injection device 900. The injection device 900 may be adapted to deliver a therapeutic compound and / or an implant device.

[0093] In the depicted embodiment, the injection device 900 comprises a sheath 902 and an injection tube 920. The injection tube 920 is slidable within a lumen defined by the sheath 902. That is, the injection tube 920 can be selectively extended distally by the clinician 1 from the distal end of the sheath 902, as depicted here in FIGS. 26 and 27 . The injection tube 920 can also be selectively retracted proximally into the sheath 902 by the clinician 1 so that it does not extend beyond the distal end of the sheath 902, as depicted here in FIG. 25 . When the injection tube 920 is extended, the exposed portion of the injection tube 920 makes up the distal end portion 910 of the injection device 900. The distal end portion 910 terminates at a beveled distal tip 912 that defines a port through which a therapeutic agent or drug is released.

[0094] The injection device 900 may have any of the features previously described in connection with the injection device 800 (including the control member), except that the injection tube 920 of the injection device 900 has only a single inherently curved portion. Nevertheless, the direction and orientation of extension of the distal end portion 910 (and distal tip 912) is substantially controllable by the clinician 1 through control factors such as the length of the distal end portion 910 and the roll, pitch, and yaw of the injection device 900 relative to the patient 10.

[0095] 28 , when open access to the pit of the round window 52 has been confirmed, an example injection instrument 800 (or any of the injection instruments described herein) may be slidably advanced by clinician 1 through a second of the TM port devices 200 while endoscope 300 is slidably positioned through a first of the TM port devices 200. A distal end portion 810 of injection instrument 800 may thereby be selectively positioned within the middle ear 40 while being directly visualized with endoscope 300. Injection instrument 800 is used to deliver a therapeutic compound or implant 100 proximate to the round window 52 (e.g., to the round window pit adjacent to the round window membrane of cochlea 50, from where the active ingredient of therapeutic compound 100 or implant 100 can passively travel by diffusion across the membrane of the round window 52) or to other target locations on or within the middle and / or inner ear regions of patient 10, as described below.

[0096] 29, under direct visualization of endoscope 300 (distal tip portion 310 is now visible), clinician 1 can controllably steer and orient distal tip portion 810 of injection tube 820 so that distal tip 812 is within or adjacent to the fossa of round window 52 (or other target location). To do so, clinician 1 can use any of the techniques described above to deflect, steer, angle, extend, and otherwise orient distal tip portion 810.

[0097] 30 , when the distal tip 812 is properly positioned relative to the round window 52 (which can be confirmed by the clinician 1 using direct visualization of the endoscope 300), the clinician 1 can deliver a desired amount of therapeutic compound 100 (or implant) to the round window pit adjacent to the round window membrane of the cochlea 50 (or other target location within the middle and / or inner ear region). This delivery can also be performed under direct visualization using the endoscope 300. That is, the clinician 1 can use the endoscope 300 to confirm that the compound or implant 100 has been delivered in the desired amount and to the desired location. Furthermore, the clinician 1 can use the endoscope 300 to monitor over a period of time to ensure that the compound or implant 100 remains in the desired location rather than migrating away from the desired location.

[0098] In certain embodiments, the delivered formulation 100 tends to remain in the desired location because the formulation 100 is delivered as a gel substance or becomes a gel substance in situ.

[0099] 31 , in certain embodiments, formulation 100 may be cured in situ (to become a gel substance) or partially cured immediately after delivery to cochlea 50. In certain such embodiments, light energy (e.g., ultraviolet light) to accelerate the curing of formulation 100 may be applied by endoscope 300 as depicted or by other instrumentation. In other embodiments, formulation 100 is a temperature-responsive hydrogel that is liquid at room temperature and forms a gel at body temperature. In other embodiments, the therapeutic formulation is chemically crosslinked at a controlled rate following mixing of the two reagents.

[0100] 32 shows example otic instrument 1200 engaged with an optionally removable sleeve device 1300. Sleeve device 1300 defines one or more auxiliary function passageways that can receive additional instruments, as further described below.

[0101] Sleeve device 1300 is removably coupled to shaft 1220 of instrument 1200. Sleeve device 1300 can have a variety of configurations (as described further below) and can be slidably engaged with and detached from shaft 1220 of instrument 1200. Sleeve device 1300 can be made from a metal (e.g., stainless steel, titanium, aluminum, etc.) or a plastic material. In some embodiments, sleeve device 1300 is transparent.

[0102] In the depicted embodiment, the otic instrument 1200 is an endoscope with a handle 1210. However, the sleeve device 1300 can be used with various other types of otic instruments, as described herein, in addition to the depicted endoscope 1200. In one example arrangement using the sleeve device 1300, the instrument 1200 is an endoscope, and an injection device can be extended through an auxiliary functional passageway defined by the sleeve device 1300. In one such embodiment, the distal tip portion of the injection device can have a natural curvature such that it can be controllably directed to a location that is non-linear with respect to the longitudinal axis of the auxiliary functional passageway.

[0103] The sleeve device 1300 can have a variety of lengths relative to the length of the shaft 1220. In some embodiments, the sleeve device 1300 will extend through the TM port device when in use. The bore of the TM port can be made to correspond to the outer shape of the sleeve device 1300 in such cases. Alternatively, the bore of the TM port device can be cylindrical with a diameter large enough to accommodate the maximum outer dimensions of the sleeve device 1300. In some embodiments, the distal end of the sleeve device 1300 is positioned proximal to the TM port device such that the sleeve device 1300 does not extend through the TM port device when in use.

[0104] Figures 33-35 are cross-sectional views of non-limiting examples of sleeve device 1300 taken at section AA. Figure 33 is a cross-sectional view of sleeve device 1300a. Figure 34 is a cross-sectional view of sleeve device 1300b. Figure 35 is a cross-sectional view of sleeve device 1300c.

[0105] Each of the sleeve devices 1300a-1300c includes a primary tube 1310 defining a lumen 1312. The lumen 1312 is configured to slidably receive the shaft 1220 of the instrument 1200 (as shown in FIG. 32 ). The sleeve devices 1300a-1300c are slidably coupled to the shaft 1220 but can be adjustably fastened at various locations along the length of the shaft 1220. In certain embodiments, a mechanism providing slight compression between the sleeve devices 1300a-1300c and the shaft 1220 can be included to adjustably fasten the sleeve devices 1300a-1300c at various locations along the length of the shaft 1220. For example, such a mechanism can include, without limitation, a collet, an annular elastomeric interface member, a wedge, a catch, a clamp, or the like.

[0106] Each of sleeve devices 1300a-1300c defines one or more auxiliary functional passageways that can receive and guide additional instruments. For example, sleeve device 1300a (FIG. 33) defines a single auxiliary functional passageway 1320a. Sleeve device 1300b (FIG. 34) also defines a single auxiliary functional passageway 1320b. Sleeve device 1300c (FIG. 35) defines a first auxiliary functional passageway 1320c and a second auxiliary functional passageway 1320d.

[0107] The auxiliary functional passageway 1320a of sleeve device 1300a is separated from the lumen 1312 by a portion of the material of sleeve device 1300a, as shown in FIG. 33. In contrast, the auxiliary functional passageway 1320b of sleeve device 1300b is merged (open, continuous) with the lumen 1312, as shown in FIG. 34. The auxiliary functional passageways 1320c and 1320d of sleeve device 1300c are separated from the lumen 1312, as shown in FIG. 35. It should be understood that any arrangement and combination of arrangements is contemplated within the scope of the present disclosure. The size and cross-sectional shape of the auxiliary functional passageways 1320a, 1320b can be fabricated in any desired manner without limitation.

[0108] FIG. 36 shows an example system including an otic instrument 1200 (e.g., an endoscope in the depicted embodiment), a sleeve device 1300 (coupled to the shaft 1220 of the endoscope 1200), and an example injection device, implant delivery device, implant refilling device, or sample extraction device 1700 that also extends through the sleeve device 1300. The injection device, implant delivery device, implant refilling device, or sample extraction device 1700 (hereinafter referred to as device 1700) represents multiple types of devices. For example, in one embodiment, device 1700 is an injection device capable of delivering a therapeutic compound to a target location in the middle ear region and / or inner ear region. In one embodiment, device 1700 is an implant delivery device capable of delivering an implant to a target location in the middle ear region and / or inner ear region. The implant can then deliver the therapeutic compound at the target location in the middle ear region and / or inner ear region. In one embodiment, device 1700 is an implant refilling device. Such an implant refilling device can deliver a replenishment of a therapeutic formulation to a previously implanted device while the device is positioned in vivo at a target location in the middle and / or inner ear region. In one embodiment, device 1700 is a sample extraction device for withdrawing tissue and / or fluid samples from a target location in the middle and / or inner ear region.

[0109] The device 1700 comprises an actuator 1710 and a shaft 1720 extending from the actuator 1710. In the depicted embodiment, the actuator 1710 is depicted as a syringe, although other types of actuators 1710 may be substituted depending on the functionality of the device 1700. The shaft 1720 is depicted as a tube, needle, or cannula, although other types of shafts 1720 may be substituted depending on the functionality of the device 1700.

[0110] In the depicted embodiment, the shaft 1720 includes a naturally curved distal tip portion (or a deflectable distal tip portion). Such a curved distal tip portion may be used to deliver therapeutic compounds, etc., on an axis offset from the main viewing axis of the endoscope 1200. Once the distal tip portion of the shaft 1720 is advanced beyond the distal tip of the endoscope shaft 1220, the shaft 1720 can be freely rotated relative to the endoscope shaft 1220. Although shown with a curved tip to the cannula, in other embodiments, the shaft is straight.

[0111] In one embodiment, as depicted in FIG. 37, the distal tip of the shaft 1720 may have a curved notch 1722 to help maintain the orientation of the tip of the shaft 1720 so that it does not rotate "outward" before passing the tip of the endoscope shaft 1220 (which could otherwise cause trauma to the tympanic membrane or other adjacent tissue if the tip of the shaft 1720 were to be extended laterally away from the endoscope shaft 1220 as it was advanced).

[0112] In some embodiments, the distal end portion of shaft 1720 may have a small gauge needle or cannula tip that is beveled, flat, rounded, side-cut, notched, atraumatic, etc., as shown in various non-exhaustive examples in FIG. 38, or may have a microneedle array as shown in FIG. 39. In other embodiments, the distal end portion of shaft 1720 may have a blunt, atraumatic, soft polymer tip. The distal end portion of shaft 1720 is configured to deliver a therapeutic compound to the middle and / or inner ear, but in some embodiments, terminates in a distal tip that can be used to extract, replace, or refill the implant device.

[0113] In other embodiments, the distal end portion of shaft 1720 terminates in a distal tip that defines a port through which suction is applied. The port at the distal tip is actuated by the device to generate suction (such as by pulling back manually or with a mechanical, electronic, pneumatic, or hydraulically assisted action on syringe 1710). In another example embodiment, device 1700 can be used to extract samples from soft tissue lesions for analysis.

[0114] 40 , in the depicted embodiment, the distal end portion of the instrument 1700 terminates in a distal tip 1724 that defines a port to which an example implant 1800 is releasably coupled. In certain embodiments, the implant 1800 may be a slip fit onto the tip 1724 of a through passage in the distal tip 1724 of the instrument 1700. In other embodiments, the implant 1800 may be retained by the cannula shaft 1720 via suction.

[0115] The instrument 1700 can be controlled by a clinician to position the distal tip 1724 and releasably coupled implant 1800 at a target location in the middle and / or inner ear. For example, in one embodiment, the distal tip 1724 and releasably coupled implant 1800 can be positioned in the round window pit, the oval window, or other portion of the cochlea through a cochleostomy.

[0116] In some embodiments, the implant 1800 may be deployed from the delivery instrument 1700 via external features on the implant 1800 that engage the target tissue and overcome a snug fit within the instrument 1700. In some embodiments, the implant 1800 may be deployed from the instrument 1700 by air pressure, by an extendable central core wire, or by actively pushing the implant 1800 from the cannula shaft 1720 by blocking suction on the shaft 1720. In some implementations, the implant 1800 is deployed entirely in the middle ear, between the middle ear and the inner ear, or entirely in the inner ear.

[0117] In certain embodiments, implant 1800 can be a solid or semi-solid having a therapeutic agent dispersed therein (example biocompatible implant materials include silicone, polyglycolide, polylactide, polycaprolactone, PEG, polyurethane, ethylene vinyl acetate). In certain embodiments, implant 1800 can be comprised of a solid drug matrix surrounded by a drug-permeable material (e.g., ethylene vinyl acetate, polyurethane) and / or a drug-impermeable material (e.g., polysulfone, polyvinyl alcohol, PMMA, polyimide, and metals such as titanium, stainless steel, nitinol, etc.).

[0118] In some embodiments, implant 1800 may be comprised of a metal or polymeric core to which a drug-eluting coating is applied. Example coating materials include, but are not limited to, biodegradable polymers such as polyphosphorylcholine, PLA, PGA, PLGA, polycaprolactone, and durable polymers such as PBMA and EVA. In some embodiments, implant 1800 may be permanent or may dissolve over time. In some embodiments, implant 1800 may include a reservoir for containing a solid, gel, or liquid therapeutic formulation of one or more therapeutic agents having one or more active ingredients.

[0119] In some embodiments, implant 1800 may include electrodes or may be a cochlear implant. In some embodiments, implant 1800 may comprise an array of microneedles that act as a permeation enhancer. In some embodiments, implant 1800 may consist of a patch that seals perilymph leaks at the oval or round window to prevent or treat perilymph fistulas.

[0120] Therapeutic formulations delivered by the devices, systems, and methods described herein may be, without limitation, gels, sprays, mist, liquids, pastes, solutions, suspensions, emulsions, etc. In certain embodiments, the therapeutic formulations may include permeation enhancers or magnetic microparticles to improve the rate of diffusion of the therapeutic agent to the inner ear. In certain embodiments, the therapeutic formulations may include lipid-encapsulated agents, microparticles, or viral vectors to improve efficiency and / or extend the duration of delivery of the therapeutic agent to the inner ear. In specific embodiments, the therapeutic formulations may include contrast agents, dyes, or stains for diagnostic imaging of the middle and inner ear. In certain embodiments, the therapeutic formulations may comprise or consist of a gel or other material that seals perilymphatic leakage at the oval or round window to treat or prevent perilymphatic fistulas.

[0121] In certain embodiments, a therapeutic formulation or otic composition (e.g., a long-release otic composition) can be delivered to a subject from or with the aid of a treatment device described herein. Such a therapeutic formulation can be delivered using an implantable therapeutic formulation carrier, such as an implant device, or by directly injecting or delivering the therapeutic formulation.

[0122] In some embodiments, the extended-release formulation may include a polymeric composition capable of forming a gel. For example, the polymeric composition may include a functionalized polymer, where the functionalized polymer includes a first functional group and a crosslinker, and the crosslinker includes a second functional group and water, such that a crosslinking reaction can occur between the first functional group and the second functional group to form a gel. In some embodiments, the functionalized polymer may be present in an amount of about 5% to about 15% by weight of the polymeric composition. In some embodiments, the crosslinker may be present in an amount of about 0.2% to about 0.6% by weight of the polymeric composition.

[0123] It is understood that the first functional group (e.g., on the functional polymer) and the second functional group (e.g., on the crosslinker) will be such that a crosslinking reaction can occur. Thus, the selection of the functional polymer can be based on the selection of the crosslinker, or vice versa. In some embodiments, the first functional group can be an N-hydroxysuccinimide (NHS) group and the second functional group can be an amine (e.g., a primary amine), or vice versa. In some cases, the functional polymer contains only electrophilic or nucleophilic functional groups, and the crosslinker contains only nucleophilic or electrophilic functional groups.

[0124] In some embodiments, the functional polymer is a multi-arm (e.g., 3-arm, 4-arm, 6-arm, or 8-arm) polyethylene glycol (PEG) containing two or more succinimidyl ester (e.g., succinimidyl succinate or succinimidyl glutarate) or sulfosuccinimidyl ester functional groups, and the crosslinker contains multiple amine (e.g., primary amine) functional groups. In some embodiments, the multi-arm PEG can have two or more arms terminating in a succinimidyl ester functional group. In some embodiments, one or a monomer of the multi-arm PEG can contain a succinimidyl ester functional group. In some embodiments, the crosslinker can be polylysine (e.g., ε-polylysine) (e.g., trilysine, tetralysine, or pentalysine). For example, in some embodiments, the functional polymer can be pentaerythritol poly(ethylene glycol) ether tetrasuccinimidyl glutarate, and the crosslinker can be trilysine.

[0125] In some embodiments, the functional polymer is a multi-armed (e.g., 3-armed, 4-armed, 6-armed, or 8-armed) polyethylene glycol (PEG) containing two or more amine (e.g., primary amine) functional groups, and the crosslinker contains multiple succinimidyl ester (e.g., succinimidyl succinate or succinimidyl glutarate) or sulfosuccinimidyl ester functional groups. In some embodiments, the multi-armed PEG may have two or more arms that terminate at an amine (e.g., primary amine) functional group. In some embodiments, one or a monomer of the multi-armed PEG may contain an amine (e.g., primary amine) functional group. In some embodiments, the crosslinker may be disuccinimidyl glutarate, disuccinimidyl suberate, bis(sulfosuccinimidyl) suberate, or disuccinimidyl succinate.

[0126] In some embodiments, the long-release otic composition can include an active agent (e.g., a therapeutic agent, a prophylactic agent, a diagnostic agent, a visualization agent, or a combination thereof). The active agent can include, for example, a protein (e.g., an enzyme, a growth factor, an antibody, or an antigen-binding fragment of an antibody), a carbohydrate (e.g., a glycosaminoglycan), a nucleic acid (e.g., an antisense oligonucleotide, an aptamer, a microRNA, a short interfering nucleic acid RNA, or a ribozyme), a small molecule, or a combination thereof. In some embodiments, the small molecule can include an antibiotic, an anti-tumor agent (e.g., doxorubicin), a local anesthetic, a steroid, a hormone, an apoptosis inhibitor (e.g., an inhibitor of Apaf-1; see, e.g., U.S. Pat. No. 9,040,701, which is incorporated by reference herein in its entirety), an angiogenic agent, an anti-angiogenic agent (e.g., a VEGF inhibitor), a neurotransmitter, a psychotropic agent, an anti-inflammatory agent, and a combination thereof.

[0127] In some embodiments, the active agent of the formulation 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, an antigen-binding fragment of an antibody, a decoy receptor, a VEGFR kinase inhibitor, an allosteric modulator of VEGFR, or a combination thereof. In some cases, the VEGF inhibitor may be an antibody or an antigen-binding fragment thereof. For example, in some embodiments, the VEGF inhibitor may be alacizumab, bevacizumab (AVASTIN®), icrucumab (IMC-18F1), ramucirumab (LY3009806, IMC-1121B, CYRAMZA®), or ranibizumab (LUCENTIS®). 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 agerafenib, altiratinib, apatinib, axitinib, cabozantinib, cediranib, lapatinib, lenvatinib, motesanib, nintedanib, pazopanib, pegaptanib, revastinib, regorafenib, semaxanib, sorafenib, sunitinib, toceranib, tivozanib, or vandetanib. Other examples of VEGF inhibitors are known in the art. In some embodiments, the VEGFR inhibitor may be an allosteric modulator of VEGFR (e.g., cyclothraxin B).

[0128] The extended release formulations or otic compositions may, in some cases, be useful for treating diseases or disorders of the ear, 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, cilia damage due to autoimmune disease, cilia damage due to infection, cilia damage due to excess fluid or pressure, chemotherapy-induced hearing loss, or a combination thereof.

[0129] Formulations that may be delivered from or with the aid of the treatment devices described herein may include, but are not limited to, antioxidants, anti-inflammatory agents, steroids, antimicrobial agents, NMDA receptor antagonists, nootropics, anti-apoptotic agents, neurotrophins, neuroprotective agents, neuroprotective proteins such as CNTF, BDNF, PEDF, NGF, cannabinoids, monoclonal antibodies, other proteins, gene therapy, iRNA, tyrosine kinase inhibitors (TKIs), dual leucine zipper kinase (DLK) inhibitors, and protein therapies such as anti-VEGF.

[0130] By way of example, the therapeutic agent of the formulation may include, but is not limited to, antibacterial agents such as antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, cephalexin, oxytetracycline, chloramphenicol, kanamycin, rifampicin, ciprofloxacin, tobramycin, gentamicin, erythromycin, and penicillin; antifungals such as amphotericin B, miconazole; sulfonamides, sulfadiazine, sulfacetamide, sulfamethizole, and sulfisoxazole; Antibacterial agents such as nitrofurazone and sodium propionate, antiviral agents such as idoxuridine, trifluorothymidine, acyclovir, ganciclovir, and interferon, antiallergic agents such as sodium cromoglycate, antazoline, methapyrilin, chlorpheniramine, pyrilamine, cetirizine, and profenpyridamine, and hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone, prednisolone, prednisolone 21-phosphate, prednisolone acetate, and fluoromethalone. Anti-inflammatory agents such as betamethasone and triamcinolone; non-steroidal anti-inflammatory agents such as salicylic acid, indomethacin, ibuprofen, diclofenac, flurbiprofen and piroxicam; decongestants such as phenylephrine, naphazoline and tetrahydrozoline; miotics and anticholinesterases such as pilocarpine, salicylic acid, acetylcholine chloride, physostigmine, eserine, carbachol, diisopropyl fluorophosphate, phosphonic acid iodide and demecarium bromide; atropine sulfate, cyclopentolate, homatropine, scopolamine, Mydriatics such as tropicamide, eucatropine, and hydroxyamphetamine, sympathomimetics such as epinephrine, antitumor drugs such as carmustine, cisplatin, and fluorouracil, immune drugs such as vaccines and immunostimulants, hormonal drugs such as estrogen, estradiol, progestational agents, progesterone, insulin, calcitonin, parathyroid hormone, peptides, vasopressin, and hypothalamic releasing factor, beta-adrenergic blocking agents such as timolol maleate, levobunolol hydrochloride, and betaxolol hydrochloride, epidermal growth factor, fibroblast growth factor,These therapeutic agents may include growth factors such as platelet-derived growth factor, transforming growth factor beta, somatotropin, and fibronectin; carbonic anhydrase inhibitors such as dichlorophenamide, acetazolamide, and methazolamide; other drugs such as prostaglandins, antiprostaglandins, and prostaglandin precursors; keratolytic agents such as selenium sulfide, imiquimod, salicylic acid, and retinoids; antioxidants; NMDA receptor antagonists; nootropics; antiapoptotic agents; neurotrophins; neuroprotective agents; tyrosine kinase inhibitors (TKIs); dual leucine zipper kinase (DLK) inhibitors; cannabinoids; monoclonal antibodies; antibody fragments; other proteins; and gene therapy. 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 with the device embodiments described herein.

[0131] Therapeutic agents in the formulations may include, but are not limited to, sodium thiosulfate for preventing cisplatin-induced hearing loss, an NMDA receptor antagonist (AM-101; Auris Medical) for the treatment of tinnitus, AM-111 (D stereoisomer of c-Jun N-terminal kinase inhibitor 1; Auris Medical) containing the synthetic peptide D-JNKI-1 for otoprotection in acute inner ear hearing loss, dexamethasone and other corticosteroids for the treatment of Meniere's disease and forms of hearing loss associated with inflammation, D-methionine (Southern Illinois University) for preventing noise-induced hearing loss, LY411575 (a selective gamma secretase inhibitor that prevents Notch activation), and NT-3 neurotrophic factor.

[0132] Therapeutic agents in the formulation may include local anesthetics for delivery to the ear canal, including, but not limited to, benzocaine, antipyrine, butamben, dibucaine, lidocaine, prilocaine, oxybuprocaine, pramoxine, proparacaine, proxymetacaine, and tetracaine.

[0133] Various pharmaceutically acceptable carriers for the therapeutic agents described herein include solids such as starch, gelatin, sugars, natural gums such as acacia, sodium alginate, carboxymethylcellulose, polymers such as silicone rubber, liquids such as sterile water, saline, dextrose, dextrose in water or saline, condensation products of castor oil with ethylene oxide, liquid glyceryl triesters of low molecular weight fatty acids, lower alkanols, mono- or diglycerides of fatty acids or phosphatides such as lecithin, polysorbate 80, etc. These may include oils such as corn oil, peanut oil, sesame oil, castor oil, etc., together with emulsifiers such as cereals, glycols and polyalkylene glycols, including P407, and other combinations of polyethylene glycol and polypropylene glycol, and aqueous media in the presence of suspending agents such as sodium carboxymethylcellulose, hyaluronic acid, sodium hyaluronate, sodium alginate, poly(vinylpyrrolidone), and similar compounds, alone or in combination with suitable dispersing agents such as lecithin, cyclodextrin, polyoxyethylene stearate, etc. The carrier may contain auxiliary substances such as preservatives, stabilizers, wetting agents, emulsifiers, or other related materials.

[0134] A therapeutic agent referenced with a trade name encompasses one or more of the therapeutic agent formulations marketed under the trade name, the active ingredient of the marketed formulation, the generic name of the active ingredient, or a molecule containing the active ingredient. As used herein, a treatment or therapeutic agent is an agent that ameliorates the symptoms of a disease or disorder, or an agent that ameliorates a disease or disorder. Therapeutic agents, therapeutic compounds, treatment regimens, or chemotherapy are known to those skilled in the art and include conventional drugs and drug treatments, including vaccines, as described elsewhere herein. Therapeutic agents include, but are not limited to, moieties capable of controlled, sustained release to the body.

[0135] Although the devices, systems, materials, compounds, compositions, articles, and methods described herein are described herein in the context of treating hearing loss, it should be understood that the devices, systems, materials, compounds, compositions, articles, and methods may be used to treat any disease of the middle and / or inner ear, including, but not limited to, tinnitus, balance disorders including dizziness, Meniere's disease, vestibular neuritis, vestibular schwannoma, otitis labyrinth, otosclerosis, ossicular chain luxation, cholesteatoma, otitis media, middle ear infection, and tympanic membrane perforation, to name a few.

[0136] While the round window membrane is one target site for delivery or access of therapeutic agents, the systems and methods described herein may be used for precise delivery of therapeutic agents to other target sites, such as the oval window or other portions 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 reconstructive surgery of the ossicular chain, cholesteatoma removal, diagnostic evaluation, and other treatment procedures. Any and all such techniques for using the systems and methods described herein are within the scope of this disclosure.

[0137] The devices, systems, materials, compounds, compositions, articles, and methods described herein can be understood by reference to the above detailed description of particular embodiments of the disclosed subject matter. However, it is understood that the above-described embodiments are not limited to specific devices, systems, methods, or specific agents, as these may vary. It is understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

[0138] Although several embodiments have been described, it will be understood that various modifications may be made without departing from the scope of the claims herein. Accordingly, other embodiments are within the scope of the following claims. [Explanation of symbols]

[0139] 1 Clinician 10 patients 20 Ear canal 30 Eardrum (TM) 32 Tympanic ring 40 Middle ear 50 Cochlea 52 Round window 100 Therapeutic preparations, implants 110 Equipment 200 Tympanic(TM) Port Device 204 Distal end section 206 Middle part 208 Proximal end portion 220 TM Port Insert 222 Delivery Sheath 224 Pushing Catheter 226 Trocar Needle 300 Endoscope 310 Distal end section 400 forceps 800 Injection equipment 802 Sheath 810 Distal end section 812 Distal tip 820 injection tube 820a, 820b, 820c tube 821a, 821b lumen 822 Linear part 823a, 823b lumen 824 First curved portion 826 Second curved section 900 Injection equipment 902 Sheath 910 Distal end section 912 Distal tip 920 Injection tube 1000 double syringe 1010 First cylindrical portion 1020 Second cylindrical part 1030 Double Plunger 1040 Y-connector 1050 static mixer 1200 Otological instruments, endoscopes 1210 Handle 1220 Shaft 1300, 1300a, 1300b, 1300c Sleeve Device 1310 Primary pipe 1312 Lumen 1320a, 1320b Auxiliary function passage 1320c First auxiliary function passage 1320d Second auxiliary function passage 1400 Tympanic Port Device 1410 Cannula Port 1412 1420 Mooring section 1422 Tip 1500 Double Tympanic Port Device 1510a first tympanic membrane port device 1510b Secondary Tympanic Port Device 1512 Connecting member 1520 Mooring section 1600 Triple Tympanic Port Device 1610a First tympanic membrane port device 1610b Secondary Tympanic Port Device 1610c Third Tympanic Port Device 1612 Connecting member 1700 Sampling Device 1710 Actuator 1720 Shaft 1722 curved notch 1724 Distal tip 1800 implants

Claims

1. 1. A system for delivering a therapeutic gel formulation to the round window pit of the cochlea under direct endoscopic visualization, said system comprising: an endoscope comprising an endoscope shaft with a distal tip portion sized to be positioned within the middle ear; 1. A sleeve device comprising: (i) a first lumen through which the endoscope shaft extends such that the distal tip portion of the endoscope can be positioned through the tympanic membrane and into the middle ear to visualize the round window pit of the cochlea while the sleeve device is generally external to the tympanic membrane; (ii) a second lumen adjacent to the first lumen; a sleeve device defining a gel injection device comprising: a proximal actuator; and an injection shaft with an injector distal tip portion defining a sidecut delivery port disposed proximal to a distal-most end of the injection shaft for dispensing a therapeutic gel formulation, the injection shaft being sized to be slidably received in the second lumen of the sleeve device, while the endoscope shaft being sized to be slidably received in the first lumen of the sleeve device; the injector distal tip portion of the gel injection device being positionable through the tympanic membrane and movable distally of the distal tip portion of the endoscope, whereby the sidecut delivery port of the gel injection device is advanceable toward the round window pit to dispense a therapeutic gel formulation therein, while the distal tip portion of the endoscope is spaced proximally from the sidecut delivery port of the injection shaft to provide visualization of the injection shaft; a gel formulation source in fluid communication with the gel injection device such that the sidecut delivery port is configured to deliver the therapeutic gel formulation at the round window pit in response to movement of the proximal actuator of the gel injection device; A system comprising: The system wherein the sleeve device is slidably coupled to the endoscope shaft and adjustably fastened in place along the length of the endoscope shaft.

2. 10. The system of claim 1, wherein the injector distal tip portion of the gel injection device is longitudinally adjustable from straight to curved to direct the sidecut delivery port toward the round window pit.

3. 3. The system of claim 2, wherein the distal injector tip portion of the gel injection device is selectively adjustable to the curved shape by manipulating one or more control members slidably coupled to the distal injector tip portion.

4. 10. The system of claim 1, further comprising a first tympanic membrane port device configured to be removably implanted in the tympanic membrane, the first tympanic membrane port device defining a port lumen, and at least one of the endoscope and the gel injection device configured to pass through the port lumen.

5. 2. The system of claim 1, wherein the sleeve device is a two-passage alignment sleeve, wherein the first lumen is a primary passageway having a first diameter, the second lumen is an auxiliary functional passageway having a second diameter smaller than the first diameter, and the second lumen is laterally spaced from the primary passageway by an intermediate wall portion of the two-passage alignment sleeve.

6. The system of claim 5 , wherein the injector distal tip portion of the gel injection device is movable relative to both the dual-channel alignment sleeve and the distal tip portion of the endoscope.

7. The system of claim 6 , wherein a proximal portion of the gel injection device disposed proximally of the dual-passage alignment sleeve has a curved shape.

8. The system of claim 7 , wherein the injection shaft of the gel injection device comprises a needle.

9. 8. The system of claim 7, wherein the endoscope shaft has an outer diameter greater than an outer diameter of the injection shaft and is sized to pass through a first incision through the tympanic membrane.

10. 10. The system of claim 9, wherein the outer diameter of the injection shaft is sized to pass through a second incision through the tympanic membrane when positioned adjacent to the endoscope shaft.

11. 11. The system of claim 10, further comprising at least one tympanic membrane port device configured to be removably implanted in the tympanic membrane, the tympanic membrane port device including a central port lumen having a diameter of 1 mm.

12. 11. The system of claim 10, wherein the endoscope shaft is positionable to pass through the tympanic membrane through an opening having a diameter of 1 mm.

13. 6. The system of claim 5, wherein the dual-passage alignment sleeve is configured to be compressed against an outer surface of the endoscope to attach the dual-passage alignment sleeve to the endoscope, while the endoscope shaft is positioned within the primary passageway, whereby the injector distal tip portion of the injection shaft is movable relative to both the dual-passage alignment sleeve and the distal tip portion of the endoscope.

14. 10. The system of claim 1, wherein the gel formulation source comprises a syringe container containing a therapeutic gel formulation including an anti-inflammatory agent.

15. 15. The system of claim 14, wherein the therapeutic gel formulation comprising an anti-inflammatory agent comprises a first functional component and a second functional component that are mixed to produce a cross-linking reaction of the therapeutic gel formulation.

16. 15. The system of claim 14, wherein the therapeutic gel formulation contained within the syringe container comprises an anti-inflammatory agent selected from the group consisting of hydrocortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, medrysone, prednisolone, prednisolone 21-phosphate, prednisolone acetate, fluoromethalone, betamethasone, and triamcinolone.

17. 15. The system of claim 14, wherein the anti-inflammatory agent of the therapeutic gel formulation is provided in an amount sufficient to passively travel by diffusion across the round window membrane into the cochlea.

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