Otological cochlear injection devices, systems and methods

Abstract

Devices, systems, and methods may be used to facilitate therapeutic procedures in the inner ear for the purposes of treating ear disorders, including, but not limited to, hearing loss and other ear disorders. In some examples, the systems and methods include instruments and techniques that may be used to minimize the invasiveness of procedures performed in the inner ear.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Application No. 63 / 249,938, filed September 29, 2021. The disclosures of the aforementioned applications are incorporated herein by reference in their entireties.

[0002] This document relates to devices, systems, and methods for facilitating therapeutic procedures in the inner ear for the purpose of treating ear disorders, including, but not limited to, hearing loss and other ear disorders. In some examples, the systems and methods include instruments and techniques that can be used to minimize the invasiveness of procedures performed in the inner ear. [Background technology]

[0003] Sensorineural hearing loss (SNHL) results from the absence or damage of hair cells in the cochlea or from impaired neural signaling downstream. SNHL is typically associated with exposure to loud noise, head trauma, aging, infection, Meniere's disease, tumors, ototoxicity, and genetic disorders such as Usher syndrome.

[0004] SNHL is common and its impact on human communication and quality of life is significant. The consequences of SNHL range from moderate communication difficulties and social withdrawal to profound hearing loss and significant disability. Conventional management of SNHL typically involves the use of hearing aids or cochlear implants.

[0005] Effective administration of therapeutic agents for the treatment of SNHL is limited by several anatomical barriers. Systemically administered agents have difficulty crossing the blood-labyrinth barrier and may require extremely high systemic doses to achieve therapeutic levels in the inner ear. Intratympanic administration may provide therapeutic exposure from diffusion across the round and oval window membranes of the cochlea. Summary of the Invention [Problem to be solved by the invention]

[0006] However, this approach may result in a concentration gradient of the therapeutic agent, leaving deeper regions of the cochlea untreated. In certain circumstances, direct administration to the round window membrane is desirable, but it currently requires highly invasive surgery that is costly and may result in complications. Therefore, a safe, effective, and minimally invasive means of administering drugs directly to the cochlea could revolutionize the field of otology and allow for the medical treatment of a variety of inner ear disorders. [Means for solving the problem]

[0007] Described herein are devices, systems, and methods for facilitating administration of therapeutic agents to the inner ear (cochlea) to treat various inner ear disorders and forms of SNHL. These inner ear disorders and forms of SNHL include idiopathic and inflammatory diseases affecting the inner ear, including autoimmune inner ear disease, chemotherapy-induced ototoxicity, and Meniere's disease. Additionally, other degenerative inner ear disorders, including idiopathic, genetically based, and age-related progressive SNHL, may be suitable for treatment with such systems. In some examples, the systems and methods include instruments and techniques that may be used to minimize the invasiveness of drug delivery or surgical procedures performed in the inner ear.

[0008] The devices, systems, and methods described herein can be used in conjunction with additional therapeutic procedures, such as, but not limited to, therapeutic delivery, including small molecules (which may be in the form of a liquid, gel, solid, etc.), proteins, and gene therapy vectors, device or implant delivery, diagnostic procedures, and surgery, among others.

[0009] In one aspect, the present disclosure relates to a method of injecting a therapeutic agent into a patient's cochlea, hi some embodiments, such a method includes advancing a shaft of an endoscope through the patient's ear canal until a distal tip of the endoscope is located in a middle ear region of the patient, advancing a microcannula defining a lumen through a working channel of the endoscope, advancing a first guidewire through the lumen of the microcannula, penetrating a round window membrane of the patient using a tip of the first guidewire, and injecting the therapeutic agent into the cochlea via the lumen of the microcannula.

[0010] Such a method for injecting a therapeutic agent into a patient's cochlea may optionally include one or more of the following features: The first guidewire may have an end having a curved shape. The method may also include advancing a microcannula over the end of the first guidewire, where as the microcannula is advanced over the end of the first guidewire, the microcannula assumes a curved shape and is aligned toward the round window membrane. The method may also include advancing the microcannula within the scala tympani of the cochlea after penetrating the round window membrane and prior to the injection. The step of advancing the microcannula within the scala tympani may be performed without advancing the first guidewire. The step of advancing the microcannula within the scala tympani may be performed while advancing the first guidewire. The step of advancing the microcannula within the scala tympani may be performed after advancing the first guidewire within the scala tympani. The method may also include withdrawing the first guidewire from the lumen of the microcannula after piercing the round window membrane and prior to injection, and inserting a second guidewire into the lumen of the microcannula. The method may also include advancing the second guidewire into the scala tympani of the cochlea after piercing the round window membrane and prior to injection. The method may also include advancing the second guidewire into the scala tympani of the cochlea over the second guidewire after advancing the second guidewire into the scala tympani of the cochlea. In some embodiments, injecting the therapeutic agent into the cochlea occurs while the first guidewire is within the lumen of the microcannula. The method may also include withdrawing the first guidewire from the lumen of the microcannula, and injecting the therapeutic agent into the cochlea occurs after the first guidewire is withdrawn from the lumen of the microcannula. The method may also include aspirating fluid from the cochlea while injecting the therapeutic agent into the cochlea. The aspirating fluid from the cochlea may be adjusted based on a fluid pressure measured within the cochlea. The aspirating fluid from the cochlea may be adjusted based on a volume balance between the therapeutic agent injected and the fluid aspirated.The microcannula may include a depth marker. The method may also include advancing the microcannula within the scala tympani of the cochlea after piercing the round window membrane and prior to injection, and using the depth marker to determine the depth to which the tip of the microcannula has been advanced within the scala tympani. The method may also include making an incision in the patient's tympanic membrane, with the shaft of the endoscope advanced through the incision.

[0011] In another aspect, the present disclosure relates to a method of injecting a therapeutic agent into a patient's cochlea, the method including advancing a shaft of an endoscope through the patient's ear canal until a distal tip of the endoscope is located in a middle ear region of the patient, advancing a microcannula defining a lumen through a working channel of the endoscope, the distal tip of the microcannula being advanced through a round window membrane and to a depth within the scala tympani of the cochlea, injecting the therapeutic agent into the cochlea via the lumen of the microcannula and while the distal tip of the microcannula is at a depth within the scala tympani, and aspirating fluid from the scala tympani during the injecting step.

[0012] Such a method for infusing a therapeutic agent into a patient's cochlea may optionally include one or more of the following features: The aspirating step may be performed using a second lumen of the microcannula. The aspirating step may be adjusted based on a fluid pressure measured within the cochlea. The aspirating step may be adjusted based on a volume balance between the therapeutic agent infused and the fluid aspirated.

[0013] In another aspect, the disclosure relates to a method of injecting a therapeutic agent into a patient's cochlea, the method comprising injecting a therapeutic agent through a microcannula and while a distal tip of the microcannula is at a depth within the scala tympani of the cochlea, and aspirating fluid from the scala tympani during the injecting step.

[0014] In another aspect, the present disclosure relates to a method of injecting a therapeutic agent into a patient's cochlea, the method including advancing a guidewire into the scala tympani of the cochlea, advancing a microcannula over the guidewire into the scala tympani to position a distal tip of the microcannula at a depth within the scala tympani, and injecting the therapeutic agent into the cochlea via a lumen of the microcannula.

[0015] In another aspect, the present disclosure relates to a medical device system including an endoscope having a distal shaft sized and configured for placement in the middle ear through an incision in the tympanic membrane, the endoscope defining a working channel, and a microcannula slidably disposable within the working channel and defining a lumen.

[0016] Such a medical device system may optionally include one or more of the following features: The medical device system may also include a disposable guidewire slidably within the lumen. The guidewire may have a curved distal end. The microcannula may have lateral conformability such that when the curved distal end of the guidewire engages within the lumen of only a portion of the microcannula, the portion of the microcannula is curved.

[0017] Some or all of the embodiments described herein may provide one or more of the following advantages. First, some embodiments of the instruments and related techniques for treating inner ear disorders described herein provide a less invasive procedure compared to conventional methods. For example, instruments and techniques are disclosed for accessing the cochlea using trans-canal and trans-tympanic approaches (as well as other approaches). Furthermore, the trans-tympanic approach may be through a small self-healing incision in the tympanic membrane. Such minimally invasive procedures may reduce overall procedure time and costs and reduce risks to the patient associated with more invasive procedures.

[0018] Second, in some embodiments, the use of the instruments and procedures described herein can treat inner ear disorders without puncturing the oval window or creating a second fenestration in the cochlea. For example, in some procedures described herein, therapeutic agents can be injected into the cochlea through the round window without affecting the oval window. Such procedures can advantageously help maintain better control of the injectate compared to procedures involving puncturing the oval window. Such procedures also reduce the risks to the patient associated with the formation of a fistula.

[0019] Third, in some embodiments, aspiration of cochlear fluid may be performed simultaneously with the infusion of therapeutic agents into the cochlea. In some such embodiments, fluid balance within the cochlea may be achieved or approximated. Thus, pressure changes within the cochlea associated with the infusion of therapeutic agents may be advantageously eliminated or tightly controlled. Such aspiration may be active or passive. Cochlear fluid collected during the procedure may be analyzed as a biomarker that may aid in the diagnosis of disease.

[0020] Fourth, the devices, systems, and methods described herein advantageously allow for the treatment of ear diseases in the cochlea without affecting the chorda tympani nerve. In contrast, some conventional methods, including the injection of therapeutic agents into the cochlea to treat ear diseases, may require the damage (e.g., cutting) of the chorda tympani nerve. The techniques described herein do not damage the chorda tympani nerve.

[0021] Fifth, the techniques described herein do not rely on diffusion of therapeutic agents across the round window membrane or diffusion of therapeutic agents within the cochlea. Instead, the techniques described herein allow for convective infusion of therapeutic agents to targeted locations deep within the cochlea and to an extent that does not rely on diffusion to produce the desired therapeutic effect.

[0022] Sixth, the systems described herein can advantageously utilize one or more guidewire properties for a variety of purposes, including, but not limited to, guiding a microcannula, adding column strength to a microcannula, penetrating or manipulating tissue.

[0023] 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 become apparent from the description and drawings, and from the claims. [Brief description of the drawings]

[0024] [Figure 1] FIG. 1 is a perspective view of an exemplary ear endoscope system according to some embodiments. [Diagram 2] FIG. 2 is a side view of the distal end of the ear endoscope system of FIG. 1, including an exemplary microcannula. [Diagram 3] 2 is another side view of the distal end of the ear endoscope system of FIG. 1, including an exemplary guidewire extending from within the microcannula. [Figure 4] 2 is another side view of the distal end of the ear endoscope system of FIG. 1 , with the microcannula advanced over the guidewire, causing the microcannula to curve according to the shape of the guidewire. [Diagram 5] FIG. 2 illustrates the ear endoscope system of FIG. 1 being used to access the round window fossa of the inner ear, according to some embodiments. [Figure 6] FIG. 2 illustrates a transtympanic incision through which the distal end of the ear endoscope system of FIG. 1 can extend to access the inner ear. [Figure 7] FIG. 1 illustrates an exemplary cochlea having a tortuous anatomical path from the round window to the inner region of the cochlea. [Figure 8A] 1 provides a flowchart of an exemplary method for injecting a therapeutic agent into the cochlea, according to some embodiments. [Figure 8B] 1 provides a flowchart of an exemplary method for injecting a therapeutic agent into the cochlea, according to some embodiments. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0025] Like reference numbers in the various drawings indicate like elements.

[0026] 1, an exemplary ear endoscope system 100 may be used to treat various ear disorders by accessing the interior of the cochlea, as described further below. The endoscope system 100 may broadly include a handle 110, an endoscope shaft 120, and a working channel access port 130. While the illustrated embodiment includes a single working channel access port 130, in some embodiments, two or more of the working channel access ports 130 may be included (with two or more working channels associated with the working channel access port 130).

[0027] An endoscope shaft 120 extends distally from the handle 110. In the illustrated embodiment, the endoscope shaft 120 extends essentially parallel to the axis of the handle 110. However, in some embodiments, the endoscope shaft 120 extends at a non-zero angle relative to the axis of the handle 110. For example, in some embodiments, the endoscope shaft 120 extends at an angle between 0° and 45° relative to the handle 110.

[0028] In some embodiments, the endoscope shaft 120 emits visible light that can illuminate the middle ear and / or inner ear during use. In some embodiments, the light can originate from an external light source and be transmitted to the distal tip of the endoscope shaft 120 via one or more optical fibers. Alternatively or additionally, in some embodiments, the light can originate from an integrated light source (e.g., LED) mounted at or near the distal tip of the endoscope shaft 120. In some embodiments, the light that illuminates the middle ear and / or inner ear can originate from a light source (e.g., optical fiber, LED, etc.) located proximal to the distal tip of the endoscope shaft 120.

[0029] In the illustrated embodiment, the ear endoscope system 100 is designed to be used with an external video display. Alternatively, in some embodiments, the ear endoscope system 100 may include an integrated lens viewing system for directly viewing the field of view of the endoscope shaft 120.

[0030] The ear endoscope system 100 also includes a working channel access port 130. The working channel access port 130 is an opening to the working channel that can receive one or more devices or instruments, as described further below.

[0031] 2-4, working channel 140 may be accessed through working channel access port 130. In this example, working channel 140 is positioned to orient a device or instrument to extend parallel to endoscope shaft 120.

[0032] In the illustrated embodiment, an exemplary microcannula 150 is slidably disposed within the working channel 140. As such, the microcannula 150 is telescopic relative to the endoscope shaft 120 (as indicated by the double arrow lines in FIG. 2).

[0033] Additionally, in this example, the ear endoscope system 100 includes an exemplary guidewire 160a (which in some embodiments may instead be a stylet and / or another microcannula). The guidewire 160a is slidably disposed within a lumen defined by the microcannula 150. In other words, the microcannula 150 is over the guidewire 160a. Thus, the guidewire 160a is retractable relative to the microcannula 150. Additionally, the microcannula 150 is retractable relative to the guidewire 160a. These movements of the microcannula 150 and / or the guidewire 160a may be manually actuated by a clinician according to known techniques.

[0034] As described further below, a variety of different guidewires may be utilized with the ear endoscope system 100. In some cases, two or more different guidewires may be used during a single procedure. Such different guidewires may have different characteristics (e.g., shape, stiffness, diameter, etc.) that may be used for specific purposes during particular stages of the therapeutic procedures described herein. Thus, guidewire 160a is merely one example of a type of guidewire that may be useful in the therapeutic procedures described herein.

[0035] As shown in Figures 3 and 4, the exemplary guidewire 160a may, but does not necessarily have, a naturally curved end. In the illustrated embodiment, the lateral stiffness of the curved end of the guidewire 160a is greater than the lateral stiffness of the microcannula 150. In other words, the microcannula 150 is more compliant than the curved end of the guidewire 160a. Thus, when the microcannula 150 is stretched distally over the curved end of the guidewire 160a, the microcannula 150 takes on the curved shape of the guidewire 160a. In this manner, the microcannula 150 is deflected or guided as the microcannula 150 is advanced. In another embodiment, the guidewire 160a does not necessarily have a greater stiffness than the microcannula 150 when stretched in air. However, once guidewire 160a is advanced (e.g., advanced into the round window cavity which requires a curved portion of guidewire 160a, as described further below) and a portion of guidewire 160a is anchored, microcannula 150 follows the path of guidewire 160a. If guidewire 160a is being used to bend, microcannula 150 follows the aforementioned path of guidewire 160a.

[0036] In another embodiment, guidewire 160a may be smaller and sized inside microcannula 150 to fit within the microcannula, and may itself have a stylet or guidewire within its lumen. In some embodiments, this inner microcannula 160a may be constructed from Nitinol and may have a preformed curve similar to guidewire 160a. In some cases, such a Nitinol inner microcannula (instead of guidewire 160a) may be advantageous because it may maintain a larger angle of curvature than guidewire 160a, thereby allowing for use in situations with tighter and / or larger bends.

[0037] 5, the ear endoscope system 100 may be used to treat the cochlea 50. The interior of the cochlea 50 (e.g., the scala tympani) may be accessed by the guidewire 160a and / or microcannula 150 of the ear endoscope system 100 through the round window 52 of the cochlea 50. In some embodiments, an injection of a therapeutic agent may be delivered into the cochlea 50 (e.g., the scala tympani) through the microcannula 150, as described further below.

[0038] As shown, the ear endoscope system 100 may be extended into the outer ear 20 of a patient 10. The microcannula 150 at the distal end of the ear endoscope system 100 and the endoscope shaft 120 may then be advanced through a small (e.g., <3 mm) incision 32 (see FIG. 6 ) in the tympanic membrane 30 and extended into the middle ear 40. In this orientation, the clinician can manipulate the microcannula 150 and / or guidewire 160a within the middle ear 40 using the endoscope shaft 120 and visualize the movement of the microcannula 150 and / or guidewire 160a as they are manipulated.

[0039] For example, in the illustrated example, guidewire 160a is extended to enter the fossa of the round window 52. This is accomplished by visualization of the clinician using the endoscope shaft 120 positioned in the middle ear 40. Furthermore, with guidewire 160a in the fossa of the round window 52, ​​the clinician can extend microcannula 150 over guidewire 160a and into the fossa of the round window 52.

[0040] In some cases, patient 10 may have a pseudomembrane over the fossa of round window 52. In such cases, guidewire 160a or another instrument may be used to puncture and / or remove the pseudomembrane (or a portion thereof) before extending guidewire 160a and / or microcannula 150 into the fossa of round window 52.

[0041] 7 shows a schematic view of a closer view of the guidewire 160a and microcannula 150 approaching the fossa of the round window 52 (as also shown in FIGS. 5 and 6). This schematic view illustrates that the path from the middle ear 40 to the cochlea 50 is a tortuous anatomical path. For example, the fossa of the round window 52 is typically approached along a first vector 51 that transverses the axis of the ear endoscope system 100. Thus, as shown, a curve in the guidewire 160a (which induces a similar curve in the microcannula 150) may be beneficial to facilitate advancement of the guidewire 160a and microcannula 150 into the fossa of the round window 52 along the first vector 51.

[0042] When the guidewire 160a and / or microcannula 150 are in the fossa of the round window 52, ​​the membrane of the round window 52 may be punctured. In some embodiments, the guidewire 160a may have a distal tip that may be used to puncture the membrane of the round window 52. For example, in some embodiments, the guidewire 160a may have a sharp distal tip or other shape to facilitate puncturing the round window membrane. In some embodiments, the guidewire 160a is advanced independently of the microcannula 150 or simultaneously with the microcannula 150 (with only the sharp tip of the microcannula 150 protruding) to puncture the round window membrane. Perforation of the round window membrane may be accomplished by advancing the guidewire 160a or by rotating the guidewire 160a to "drill" through the round window membrane.

[0043] As described elsewhere herein, in some embodiments, rather than a guidewire 160a, a second, inner microcannula is used inside the main microcannula 150. In such cases, the microcannula 160a may have a sharp edge at its distal tip and may be gently rotated to drill through the round window membrane.

[0044] After puncture of the round window membrane, a guidewire 160a (which may also represent a stylet or inner microcannula 160a) may be advanced through the round window membrane. The microcannula 150 may be simultaneously or subsequently advanced through the round window membrane over the guidewire 160a. If necessary, the guidewire 160a may be exchanged for another guidewire 160a if it is desired, for example, to remove a sharp tip or to change to a guidewire having different characteristics (e.g., guidewire stiffness, preformed curvature, etc.).

[0045] After puncturing the membrane of the round window 52, ​​to advance the microcannula 150 into the scala tympani 54 of the cochlea 50, the extension and advancement direction of the microcannula 150 is adjusted from the first vector 51 to approximately coincide with a second vector 53 extending along the scala tympani 54. Typically, the first vector 51 and the second vector 53 are significantly different (as shown in FIG. 7 ). Thus, the microcannula 150 undergoes a significant change in direction (curve) as it is extended from its entrance at the round window 52 into the scala tympani 54. In some cases, this curvature may be performed by first extending the guidewire 160a (and its curved end) into the scala tympani 54 and then extending the microcannula 150 over the guidewire 160a. In some cases, the guidewire 160a may be withdrawn and a second guidewire 160b (not shown) may be inserted through the microcannula 150. Second guidewire 160b may have different characteristics than guidewire 160a, such as a curved portion having a different radius than the curved portion of guidewire 160a.

[0046] In some embodiments, after puncturing the membrane of the round window 52, ​​the microcannula 150 may be advanced by itself into the scala tympani 54 (without having a guidewire at the end of the microcannula 150). In such a case, the high conformability or flexibility of the microcannula 150 may allow the microcannula 150 to easily follow the anatomy of the scala tympani 54 as it is advanced within the scala tympani 54. Furthermore, in some embodiments, the distal tip of the microcannula 150 may be configured atraumatically (e.g., to have a donut-shaped tip at its distal tip) to avoid damaging the wall of the scala tympani 54 as the microcannula 150 is advanced within the scala tympani 54.

[0047] In some embodiments, the microcannula 150 can be 39-40 gauge (outer diameter approximately 0.12 mm). In some embodiments, the outer diameter of the microcannula 150 can be 0.12 mm to 0.4 mm. In certain embodiments, the microcannula 150 can have a graduated gauge (diameter) such that the tip is smaller than the proximal portion of the microcannula 150. The graduated change in diameter of the microcannula 150 can be incremental (step change) or continuous (gradual change).

[0048] Whatever the most appropriate method, the microcannula 150 may be advanced fully into the scala tympani 54. Due to the shape of the cochlea 50, during advancement of the microcannula 150 within the scala tympani 54, the microcannula 150 changes or turns from extending along the second vector 53 to extending along a third vector 55 (and then extending along the other direction defined by the helical shape of the scala tympani 54) as the microcannula 150 is advanced. In some embodiments, the microcannula 150 may have a lubricious coating to facilitate its advancement. In some embodiments, the microcannula 150 may have a non-circular cross-sectional shape (e.g., D-shaped, oval, etc.).

[0049] The microcannula 150 may be advanced to a desired depth within the scala tympani 54. In some embodiments, depth markers may be included on the microcannula 150 to allow the clinician to insert the microcannula 150 into the scala tympani 54 to a target depth (or target depth range) within the cochlea 50. Research by the inventors has shown that the tip of the microcannula 150 does not have to be placed all the way into the tip of the cochlea 50. Instead, the inventors have found that a depth location well within the audio range, for example between an 8000 kHz frequency location (approximately 10 mm from the tip of the cochlea 50) and a 600 Hz frequency location (approximately 25 mm from the tip of the cochlea 50), is a good target depth for injecting the therapeutic agent. Such a depth is sufficient, for example, because the inventors have also found that the injection includes a jetting action (or convection), which may allow the therapeutic agent to reach beyond the distal tip of the microcannula 150 during injection. For example, using several displacement configurations (e.g., using flow rates between 1 cc / min and 2.5 cc / min with a 0.13 mm ID x 0.26 mm OD microcannula), the inventors have achieved convective mixing up to 15 mm beyond the distal tip of the microcannula 150 (although the inventors can envision flow rates as low as 5 microliters / min to 50 microliters / min, with microcannula sizes between 0.12 mm and 0.9 mm OD).

[0050] Once the microcannula 150 has been inserted to the target depth within the scala tympani 54, injection of a therapeutic agent through the microcannula 150 may begin. In some embodiments, the guidewire (if still present within the microcannula 150 at this stage) is first removed from the lumen of the microcannula 150 prior to injection. In certain embodiments, the guidewire (if still present at this stage) is left within the lumen of the microcannula 150 during injection.

[0051] In some embodiments, during the infusion of a therapeutic agent into the cochlea 50 via the microcannula 150, natural fluids from the cochlea 50 may be simultaneously aspirated. Thus, in some embodiments, the microcannula 150 may be configured with a second lumen having one or more openings located proximal to the distal tip of the microcannula 150. In other words, in some embodiments, the microcannula 150 is a multi-lumen catheter having a first lumen for infusion and a second lumen for aspiration. One or more openings to the second lumen may be located proximal to the distal tip of the microcannula 150 (e.g., near the round window 52) such that a length of the scala tympani 54 along the catheter is exposed to the infused agent. The two lumens of such a multi-lumen microcannula 150 may have various cross-sectional shapes and configurations (e.g., a C-shaped cross-section adjacent to a circular cross-section, two circular cross-sections, or other shapes). In other embodiments, the multi-lumen microcannula 150 may have two nested tubular structures such that the second lumen is concentric with the main lumen. The multi-lumen microcannula 150 may be constructed from two coaxial tubes such that infusion can occur through the central tube and aspiration can occur simultaneously through the annular space around the central tube (e.g., either the distal opening or a side opening of an outer tube located proximally to the distal tip of the central tube).

[0052] Such suction during injection can help prevent a potentially dangerous rise in intracochlear pressure. In some embodiments, pressure measurements are taken at the scala tympani 54 during injection and can be used to adjust the amount of suction to keep the intracochlear pressure within a target range. In some embodiments, such a pressure sensor can be placed on the microcannula 150 or on a guidewire within the scala tympani 54.

[0053] In some embodiments, fluid balance techniques can be used to regulate / control the amount of aspiration during infusion, i.e., the volume of aspiration can be measured and controlled to remain essentially equal to the volume of infusion.

[0054] The injected fluid may include therapeutic agents such as, but not limited to, small molecules, large molecule biologics, peptides, oligonucleotides, and gene therapy vectors. The injected fluid may also include tracer molecules to aid in the diagnosis of pathology, such as iodine-based agents to enhance X-ray and CT imaging, and gadolinium-based contrast agents to enhance MRI images.

[0055] The system allowing for aspiration during infusion also allows for the safe collection of native perilymph fluid. This fluid bathes the scala tympani and contains molecular markers that can be used to inform disease diagnosis, disease prognosis, disease stage, and response to intervention. The collected fluid can be analyzed for the presence, absence, and relative quantitative expression of various molecules, including nucleic acids, peptides, proteins, lipids, ions, and other small molecules, using established techniques. It is expected that the concentration of perilymph in the collected fluid will decrease over time during the procedure as it is diluted with the infused agent. A series of collection reservoirs can be installed to separate the collected fluid by collection time. Early samples, enriched in perilymph, can be preferentially analyzed for the presence of biomarkers to increase the likelihood of detection and quantification.

[0056] A system that allows for aspiration during injection also allows for safe collection of the injected drug. Conversely, a system that allows for outflow from a second fenestration in the cochlea or backflow from the round window would result in exposure of the injected drug to the middle ear tissue and the Eustachian tube, further increasing systemic exposure. Especially in the case of gene therapy, limiting exposure outside the cochlea is highly desirable to limit immune responses to the drug.

[0057] 8A and 8B, a method 200 for injecting a therapeutic substance into a patient's cochlea is shown in flow chart form. Method 200 may be performed in the manner and using the devices and systems described above. The dashed boxes are optional steps.

[0058] At step 210, an incision or opening is made in the patient's tympanic membrane. Such an incision is illustrated in FIG. 6 (see incision 32 in tympanic membrane 30). In some cases, the incision may be less than 2 mm in length. In certain circumstances, a port device may be placed in the incision. Such a port device present in the incision may define an opening through which instruments may extend to access the middle ear. Alternatively, in some embodiments, rather than an incision, a small flap of tympanic membrane 30 may be raised.

[0059] In step 220, one or more devices may be advanced through the tympanic membrane incision (or opening formed by the tympanic membrane flap) and toward the round window fossa. For example, as shown and described with reference to FIGS. 5-7, in some embodiments, an endoscope, a microcannula, and a guidewire may be advanced through the tympanic membrane incision. In some embodiments, one or more stabilizing devices (e.g., collars, guides, passageways, or tubes that are temporarily secured to the patient's anatomy and define one or more channels for slidably receiving instruments) may be used at the ear canal and / or tympanic membrane. One or more devices (e.g., an endoscope, a microcannula, and a guidewire) may be advanced through such stabilizing devices. The stabilizing devices may improve control of the one or more devices and improve patient safety. As a result, the distal ends of the microcannula and the guidewire may be positioned in the patient's middle ear. To the extent achievable, an endoscope may be positioned to facilitate visualization of the round window fossa.

[0060] During step 220, in some embodiments, a microcannula may be placed in the working channel of the endoscope and a guidewire may be placed in the lumen of the microcannula. The microcannula may be movable distally and proximally relative to the endoscope. Additionally, the guidewire may be movable distally and proximally relative to the microcannula. In other words, the microcannula is movable over the guidewire.

[0061] If the patient has a pseudomembrane or other obstruction to the round window fossa, the pseudomembrane or other obstruction may be removed or alleviated at least to the extent necessary to gain access to the round window fossa.

[0062] In some embodiments, the guidewire may include one or more ends that are curved or shaped (e.g., as shown in FIG. 3) to direct the guidewire toward the round window fossa. When the microcannula is advanced over (or resides on) the curved or shaped portion of the guidewire, the microcannula will tend to follow the curved or shaped portion of the guidewire (e.g., as shown in FIGS. 4 and 7). Thus, the guidewire may be used to "steer" the microcannula.

[0063] In step 230, the microcannula is advanced over the guidewire into the round window fossa toward the round window membrane, which provides a barrier between the round window fossa of the cochlea and the scala tympani. The distal tip of the guidewire and / or microcannula is now within the round window fossa.

[0064] At step 240, the round window membrane is pierced by the distal tip of the guidewire. In some embodiments, the guidewire may have a tip that is specifically configured to pierce the round window membrane. For example, in some embodiments, the tip of the guidewire may be pointed, sharp, and / or rigid to facilitate piercing the round window membrane. A microcannula may be near the tip of the guidewire at this junction to provide additional column strength to the guidewire to aid in piercing the round window membrane. In some embodiments, the round window membrane may be pierced in other ways (other than by the distal tip of the guidewire). For example, in some embodiments, the round window membrane may be pierced using another type of instrument, such as a laser, ultrasonic instrument, etc.

[0065] With the round window membrane punctured, the distal tip of the guidewire and / or microcannula may be advanced through the puncture and into the scala tympani of the cochlea. In some embodiments, a cochlear fenestration (cochleostomy) may be created as an alternative entry point to the round window membrane. The cochleostomy may be created via a small drill, laser, ultrasonic instrument, or the like. Placement of the microcannula through the cochleostomy may reduce the degree of guidance required to enter the basal bend of the cochlea, facilitating insertion.

[0066] In optional step 250, the guidewire (i.e., the "first guidewire") is withdrawn and another guidewire (i.e., the "second guidewire") having different properties than the first guidewire may be advanced through the lumen of the microcannula (while the microcannula remains in its current position). For example, in some embodiments, the second guidewire may have a curved portion with a different radius than the first guidewire. In such a case, the second guidewire may facilitate guiding the tight bend required to advance the microcannula from aligned with the first vector 51 to aligned with the second vector 53 (see FIG. 7). Additionally, in some embodiments, the second guidewire may have an atraumatic tip (e.g., instead of a tip configured to puncture the round window membrane as the first guidewire may have). In some embodiments, there may be multiple guidewire changes to accommodate multiple bends in the scala tympani.

[0067] Steps 260, 262, and 264 are three alternative techniques for advancing the microcannula into the scala tympani. In some embodiments, a combination of these three techniques may be used. In certain embodiments, the microcannula and / or guidewire may include depth markers that provide the clinician operator with an indication of the distance the microcannula and / or guidewire has been extended into the scala tympani.

[0068] At step 260, the microcannula is advanced along the scala tympani without advancing a guidewire. In other words, the microcannula is advanced along the scala tympani by itself. In some aspects, the microcannula may have a high degree of conformability that allows the microcannula to follow the curvature of the scala tympani as it is advanced. Additionally, in some embodiments, the microcannula has an atraumatic tip to reduce the risk of damaging the inner wall surface of the cochlea as the microcannula is advanced.

[0069] In step 262, the microcannula is advanced along the scala tympani while the guidewire resides within the lumen of the microcannula. In other words, the microcannula and the guidewire are advanced simultaneously along the scala tympani.

[0070] In step 264, the guidewire is first advanced along the scala tympani by itself and then the microcannula is advanced over the guidewire.

[0071] The microcannula may be advanced to a particular target depth (or target depth range) within the cochlea. Generally, the tip of the microcannula may be inserted to a point between the round window and the apex of the cochlea. For example, in some cases, the tip of the microcannula may be inserted from the round window into the cochlea (scala tympani) a distance of, but not limited to, 10 mm to 15 mm, or 8 mm to 20 mm, or 12 mm to 24 mm, or 16 mm to 30 mm.

[0072] The guidewire within the lumen of the microcannula is optionally withdrawn at step 270. However, in some embodiments, the guidewire is left within the lumen of the microcannula.

[0073] A therapeutic agent is injected or infused into the cochlea through the lumen of the microcannula, step 280. The infusion may provide a convection jet effect, where the infusate (therapeutic agent) is injected far beyond the tip of the microcannula toward the apex of the cochlea.

[0074] In optional step 290, fluid from within the cochlea may be aspirated while the therapeutic agent is being infused into the cochlea. Such simultaneous aspiration during infusion may help maintain intracochlear fluid pressure within a target range. Aspiration may be active or passive. In some embodiments, pressure measurements in the scala tympani may be taken during infusion and used to adjust the amount of aspiration to keep the intracochlear pressure within a target range. In some embodiments, such a pressure sensor may be placed on the microcannula or on the guidewire within the scala tympani. In some embodiments, a fluid balance technique may be used to adjust / control the amount of aspiration during infusion. That is, the aspiration volume may be measured and controlled to remain essentially equal to the infusion volume.

[0075] To facilitate the aspiration of step 290, in some embodiments, the microcannula is a multi-lumen catheter having a first lumen for infusion and a second lumen for aspiration. One or more openings to the second lumen are positioned proximally (e.g., near the round window) such that fluid aspirated from the scala tympani is not (or contains only small amounts of) therapeutic agent. In some embodiments, a second cannula may be used to aspirate fluid from the scala tympani near the round window.

[0076] In step 300, the device is withdrawn and completely removed from the patient. The therapeutic agent injected into the cochlea remains within the cochlea to provide its therapeutic effect. The small incision into the tympanic membrane 30 is self-healing and will close on its own over a period of time.

[0077] Although the above-described method 200 of injecting a therapeutic substance into a patient's cochlea uses an endoscope for direct visualization, in some embodiments, a microscope or an OCT (optical coherence tomography) scope may be used instead of or in addition to such an endoscope. Some such cases may include the use of an instrument (i.e., a catheter guide) having a small mirror to provide visualization of the round window using the microscope (i.e., a small mirror). Thus, in some embodiments, an endoscope is not required to perform the method 200.

[0078] Although the instruments disclosed herein are primarily described in the context of otologic procedures using transcanal, transtympanic approaches to the middle or inner ear, it should be understood that the instruments are not limited to such use and may be used for other cavities or spaces within the body and other approaches. For example, in some embodiments, the instruments described herein may be used for other approaches and procedures to the middle ear, inner ear, Eustachian tube, mastoid cavity, including, but not limited to, transmastoid access, transcanal via mesotympanic flap, transtympanic annulus, endometrial, posterior ear, ear posturing, cochlear anastomosis, etc. Such systems and methods may be used for drug delivery, gel delivery, antibiotic delivery, gene delivery, graft placement, device or implant delivery, tissue removal, diagnostic procedures, harvesting procedures, surgery, among others.

[0079] It should be noted that any of the embodiments or features of the embodiments described herein may be combined in any combination and any permutation, all within the scope of the present disclosure.

[0080] The devices, systems, and methods described herein can be used in the course of treating any disorder of the middle and / or inner ear, including, but not limited to, hearing loss, tinnitus, balance disorders including vertigo, Meniere's disease, vestibular neuritis, vestibular schwannoma, labyrinthitis, otosclerosis, ossicular chain luxation, cholesteatoma, otitis media, middle ear infection, and tympanic membrane perforation, to provide a few examples. In some embodiments, the devices, systems, and methods described herein can be used in the course of precise delivery of therapeutic agents to the round window fossa and / or other target sites, such as the oval window or other parts of the middle ear cavity, and to provide access to other features or regions of the middle ear. For example, the systems and methods described herein can be used in minimally invasive reconstructive surgery of the ossicular chain, removal of cholesteatomas, diagnostic evaluations, and other procedures. Any such techniques for using the systems and methods described herein are within the scope of this disclosure.

[0081] The devices and systems described herein may be constructed from metals, such as but not limited to aluminum, titanium, stainless steel, nitinol, braided combinations thereof, or polymers, such as but not limited to silicone, polyurethane, ABS, PEEK, PET, HDPE, injection molded parts, elastomeric materials, gels, and the like.

[0082] The devices, systems, materials, compounds, compositions, articles, and methods described herein can be understood by reference to the above detailed description of certain aspects of the disclosed subject matter. However, it should be understood that the above aspects are not limited to specific devices, systems, methods, or specific intermediaries, and thus may vary. It should also be understood that the terminology used herein is for the purpose of describing certain aspects only, and is not intended to be limiting.

[0083] 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]

[0084] 10 patient, 20 outer ear, 30 tympanic membrane, 32 incision, 40 middle ear, 50 cochlea, 51 first vector, 52 round window, 53 second vector, 54 scala tympani, 55 third vector, 100 ear endoscope system, 110 handle, 120 endoscope shaft, 130 working channel access port, 140 working channel, 150 microcannula, 160a guidewire, 160b second guidewire

Claims

1. 1. A system for injecting a therapeutic agent into a cochlea, comprising: The system comprises: an endoscope having a shaft sized for advancement through the ear canal and tympanic membrane, such that a distal tip of the endoscope is positionable within the middle ear region for visualization of the cochlea; a therapeutic agent for delivery into the cochlea; a microcannula including a cochlear delivery lumen, a proximal port in fluid communication with the cochlear delivery lumen and configured to receive the therapeutic agent for delivery into the cochlea, and a distal port adjacent to the shaft of the endoscope and movable relative to the endoscope for advancement through the tympanic membrane, wherein the distal port of the microcannula is insertable into the cochlea under visualization from the endoscope; a first guidewire slidable within the microcannula, the first guidewire having a guidewire tip configured to pierce a round window membrane of the cochlea while at least a portion of the first guidewire is disposed within the microcannula, the distal port of the microcannula being insertable through the round window membrane pierced by the guidewire tip to inject the therapeutic agent into the cochlea via the cochlear delivery lumen of the microcannula; A system comprising:

2. 2. The system of claim 1, wherein the first guidewire has an end portion having a curved shape, and the microcannula is flexible to assume the curved shape of the end portion of the first guidewire in response to advancing the microcannula over the end portion of the first guidewire, and the microcannula is aligned toward the round window membrane.

3. 3. The system of claim 1 or 2, wherein the distal port of the microcannula is insertable into the scala tympani of the cochlea through the round window membrane pierced by the guidewire tip.

4. 4. The system of claim 3, wherein the distal port of the microcannula is insertable into the scala tympani while the guidewire tip of the first guidewire remains proximal from the scala tympani.

5. 4. The system of claim 3, wherein the distal port of the microcannula and the guidewire tip of the first guidewire are simultaneously insertable into the scala tympani.

6. 4. The system of claim 3, wherein the distal port of the microcannula is insertable into the scala tympani by advancement of the microcannula over the first guidewire while the guidewire tip of the first guidewire is positioned within the scala tympani.

7. 3. The system of claim 1, wherein the first guidewire is retractable from the microcannula, and the system further includes a second guidewire insertable into the microcannula following retraction of the first guidewire from the microcannula.

8. 8. The system of claim 7, wherein the second guidewire has a different shape than the first guidewire, and the second guidewire is configured for insertion into the scala tympani of the cochlea.

9. 9. The system of claim 8, wherein the distal port of the microcannula is insertable into the scala tympani by advancement of the microcannula over the second guidewire while the second guidewire is positioned within the scala tympani.

10. 3. The system of claim 1 or 2, wherein the distal port of the microcannula is configured to inject the therapeutic agent into the cochlea through the cochlear delivery lumen of the microcannula while the first guidewire is positioned within the microcannula.

11. 3. The system of claim 1 or 2, wherein the distal port of the microcannula is configured to inject the therapeutic agent into the cochlea through the cochlear delivery lumen of the microcannula after the first guidewire is withdrawn from the microcannula.

12. 3. The system of claim 1 or 2, wherein the microcannula is configured to aspirate fluid from the cochlea during infusion of the therapeutic agent into the cochlea.

13. 13. The system of claim 12, wherein the microcannula is configured to aspirate fluid from the cochlea in response to fluid pressure measured in the cochlea.

14. 13. The system of claim 12, wherein the microcannula is configured to aspirate the fluid from the cochlea according to a volume balance between the therapeutic agent infused and the fluid aspirated.

15. The system of claim 1 or 2, wherein the microcannula includes a depth marker positioned proximate the distal port for visualization from the endoscope.

16. 16. The system of claim 15, wherein the depth marker indicates the depth to which the distal port of the microcannula is advanced within the scala tympani.

17. 3. The system of claim 1 or 2, wherein the shaft of the endoscope is sized to be advanced through an incision in the tympanic membrane that is less than 2 mm in length.

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