EA046366B1 - DEVICE FOR DELIVERY OF LIQUID INTO THE EAR AND SYSTEM CONTAINING SUCH DEVICE (VERSIONS) - Google Patents

Description

Cross references to related applications

This application claims priority to US Provisional Patent Application No. 63/030519, filed May 27, 2020; No. 63/126270, filed December 16, 2020; and No. 63/151610, filed February 19, 2021 - all of which are entitled DEVICES, SYSTEMS, AND METHODS FOR DELIVERING FLUID TO THE INNER EAR, the contents of which are incorporated herein by reference in their entirety.

State of the art

Delivery of drugs to the inner ear presents significant challenges. The corresponding organs are located deep in the skull, enclosed in bone and isolated from the circulatory system by the blood-labyrinth barrier. Some organs of the inner ear, including the organ of Corti, are particularly inaccessible and fragile.

Fluids containing drugs can be delivered into the middle ear cavity in the hope that they will diffuse through the round window membrane (RWM) into the inner ear. However, only a very small percentage of the administered fluid and medication actually enters the fluid space of the inner ear. Distribution throughout the inner ear is usually based on simple diffusion, which results in the delivered fluid and drug being highly diluted by the time it reaches its target site of action in the inner ear.

Brief description of the invention

The disclosed embodiments include devices, systems and methods for delivering fluids to the inner ear. The devices, systems and methods described herein include a device that introduces fluid into the perilymphatic fluid of the inner ear. In some embodiments, the described devices, systems and methods have potential advantages over existing devices, systems and methods with respect to both the safety and effectiveness of the intracochlear medicinal fluid.

In some embodiments, design elements of the described devices and systems include maintaining sterility of the administered fluid; minimizing bubbles introduced into the inner ear; the ability to accurately deliver small volumes at a controlled flow rate (for example, in combination with the use of a standard pump); allowing visualization of the round window membrane (RWM) during delivery through the external auditory canal by the surgeon; minimizing damage to the RWM or inner ear structures outside the RWM; and minimizing test drug leakage through the RWM.

In one aspect of the present invention, there is provided a device for delivering fluid to the ear, comprising: a handle portion having a proximal end and a distal end; a needle subassembly connected to the distal end of the handle portion and containing a curved needle; and a tube connected to the proximal end of the handle portion. A curved needle extends through the handle portion and is fluidly connected directly to the tubing.

In some embodiments, the device includes a telescopic support connected to the proximal end of the needle subassembly.

In some embodiments, the distal end of the handle is connected to the proximal end of the telescopic support.

In some embodiments, the telescopic support includes a plurality of hypotubes inserted into each other.

In some embodiments, the curved needle includes: an angled tip for piercing at least one membrane and a curved portion.

In some embodiments, the device includes a strain relief element coupled to the proximal end of the handle portion.

In some embodiments, the device includes a camera (eg, a distal tip camera). The distal tip chamber is located inside the needle subassembly.

In some embodiments, the tube is connected to a curved needle in the hollow interior of the pen portion.

In some embodiments, the device has an internal diameter of from about 0.005 inch to about 0.01 inch.

In some embodiments, the curved portion has a length of from about 0.5 mm to about 5 mm (eg, from about 1 mm to about 3 mm, such as about 1.4 mm).

In some embodiments, the angle is from about 20 degrees to about 70 degrees (e.g., from about 20 degrees to about 60 degrees, e.g., from about 20 degrees to about 50 degrees, e.g., from about 20 degrees to about 40 degrees, e.g. about 30 degrees, for example about 30 degrees to about 70 degrees, for example about 40 degrees to about 60 degrees, for example about 55 degrees).

In some embodiments, the angle is about 30 degrees.

- 1 046366

In some embodiments, the angle is about 55 degrees.

In some embodiments, the curved needle has a gauge ranging from about 10 to about 35, such as about 20 to about 35, such as about 30 to about 35, such as 33 gauge.

In some embodiments, the curved needle is at least partially composed of stainless steel.

In some embodiments, the device includes an adhesive located at the proximal end and the distal end of the handle portion.

In some embodiments, the device includes a stopper coupled to a curved needle. The stopper is shaped and sized to fit into the inner ear and control the distance the angled tip protrudes into the cochlea.

In some embodiments, the restrictor is shaped like a cylinder with a disk.

In some embodiments, the stopper is molded in place onto the curved needle and prevents the curved needle from being inserted into the at least one membrane beyond a desired amount.

In some embodiments, the stopper is located at a distance of from about 0.2 mm to about 1.2 mm (for example, from about 0.4 mm to about 1.0 mm, for example, from about 0.6 mm to about 0.9 mm eg about 0.85 mm) from the distal end of the angled tip.

In some embodiments, the stopper has a diameter of from about 0.2 mm to about 1.2 mm (e.g., from about 0.4 mm to about 1.0 mm, e.g., from about 0.6 mm to about 0.9 mm, for example about 0.85 mm).

In some embodiments, the stopper has a height of from about 0.2 mm to about 1.0 mm (e.g., from about 0.3 mm to about 0.7 mm, e.g., from about 0.4 mm to about 0.6 mm, for example about 0.5 mm).

In some embodiments, each hypotube of a plurality of interstitial hypotubes has a gauge of from about 10 to about 30 (eg, 14XH, 20TW, 23XTW, and/or 27TW).

In some embodiments, each hypotube of a plurality of interstitial hypotubes comprises stainless steel.

In some embodiments, the handle portion further includes a conical portion located at a distal end of the handle, wherein the telescopic support is coupled to the conical portion. The handle tapers toward the first distal end (eg, such that the second proximal end of the telescopic support is connected to the first distal end).

In some embodiments, the telescopic support tapers from an outer diameter of about 0.2 inches or less at the proximal end to an outer diameter of about 0.01 inches or more at the distal end.

In some embodiments, the handle portion includes machined grooves to provide tactile sensitivity and control.

In some embodiments, the handle portion is shaped and sized to facilitate placement in the inner ear.

In some embodiments, the strain relief member comprises laminated projections (eg, Pebax laminated projections).

In some embodiments, the strain relief element prevents kinks and/or deformation of the tube.

In some embodiments, the tubing is connected to the curved needle through a compression fit.

In some embodiments, the tube comprises polyetheretherketone (PEEK).

In some embodiments, the tube has an internal diameter of from about 0.003 inch to about 0.01 inch (eg, about 0.007 inch).

In some embodiments, the tube has an outer diameter of from about 1/64 inch to about 1/16 inch (eg, about 1/32 inch).

In some embodiments, the tube is longer than 20 inches, such as greater than 30 inches, such as greater than 40 inches, such as greater than 50 inches, such as greater than 60 inches, such as about 60 inches.

In some embodiments, the device is sterile and/or biocompatible.

In some embodiments, the angled tip protrudes from the curved portion of the curved needle to form an outlet for dispensing fluid.

In another aspect of the present invention, there is provided a system comprising a device and a sterile syringe in fluid communication with tubing.

In some embodiments, the system includes a pump.

In some embodiments, the pump controls the rate of fluid flow through any of the devices (e.g., at about 10 μL/min to about 60 μL/min, e.g., about 15 μL/min to about 55 μL/min, e.g., about 20 μL/min to about 50 μL/min, for example, from about 25 μL/min to about 45 μL/min, for example, from about 25 μL/min to about 40 μL/min, for example, from about 20 μL/min to about 35 μl/min, for example, about 30 μl/min) (for example, at a level of about 10 μl/min to about

- 2 046366

200 μl/min, for example, from about 20 μl/min to about 180 μl/min, for example, from about 30 μl/min to about 180 μl/min, for example, from about 40 μl/min to about 150 μl/min, for example, from about 50 μl/min to about 150 μl/min, for example, from about 60 μl/min to about 140 μl/min, for example, from about 70 μl/min to about 130 μl/min, for example, from about 80 µL/min to about 120 µL/min, for example about 90 µL/min to about 110 µL/min, for example about 100 µL/min).

In some embodiments, the stopper is located around a stopper attachment slot located within the curved needle.

In some embodiments, the device includes a ring reinforcement located at the interface between the telescopic support and the handle portion.

In some embodiments, the device includes at least one machined boss located at the proximal end of the handle portion.

In some embodiments, the machined boss cooperates with the strain relief and prevents axial movement between the handle portion and the strain relief.

In another aspect of the present invention, a delivery system is provided, comprising: a delivery device including a distal end; and a stop located at the distal end of the delivery device; a distal tip camera located at a distal end of the delivery device, the distal tip camera comprising an image sensor; and a monitor operatively coupled to the distal tip camera. The monitor displays information received from the distal tip camera.

In some embodiments, the limiter is transparent.

In some embodiments, the stopper includes a transparent portion to allow the camera to view the distal tip through the stopper.

In some embodiments, the distal tip chamber is located above the front surface of the stopper and the front surface of the stopper faces the target site.

In some embodiments, the target site is a portion of the ear.

In some embodiments, the distal tip camera is built into (eg, integrated) into the stopper.

In some embodiments, the distal tip chamber is located behind the stopper.

In some embodiments, the delivery system includes a wire that is operably connected between the distal tip camera and the monitor.

In some embodiments, the distal tip camera has autofocus capabilities.

In some embodiments, the distal tip chamber has at least one of a cuboid shape, a plate shape, a cylindrical shape, or a combination thereof.

In some embodiments, the image sensor has a field of view of about 90° to about 150°.

In some embodiments, the image sensor has a cuboidal shape with dimensions up to 10 mm x 10 mm and a height of up to 100 mm and/or a cylindrical shape with an outer diameter of up to 10 mm and a length of up to 100 mm.

In some embodiments, the image sensor includes an imaging array capable of capturing video at a resolution of at least 10x10 pixels at a frame rate of at least 5 frames per second.

In some embodiments, the image sensor has an image area of no more than 10 mm x 10 mm.

In some embodiments, the image sensor has an optical format of up to 10 mm and a pixel size of up to 10 μm.

In some embodiments, the delivery system includes a processor operably coupled to an image sensor.

In some embodiments, the delivery system contains driver packages and/or software packages.

In some embodiments, the delivery system includes at least one light source.

In some embodiments, the delivery system comprises an optical fiber.

In another aspect of the present invention, there is provided a distal tip camera system comprising: an image sensor located at the distal end of a needle containing a stopper; a wire operatively connected to the image sensor; a processor operatively coupled to the image sensor; and a monitor operatively coupled to the processor for displaying information captured by the image sensor and processed by the processor.

In another aspect of the present invention, there is provided a surgical procedure for delivering a therapeutic fluid to a portion of the inner ear (eg, using any of the devices described herein), comprising: operating a posterior tympanomeatal flap; Creation

- 3 046366 holes in the base of the stirrup; piercing the round window with a needle located at the distal end of the fluid delivery device; positioning the fluid delivery device at the desired insertion depth in the circular window; and passing the therapeutic fluid through the fluid delivery device into the inner ear.

In some embodiments, the procedure includes: activating the distal tip camera, endoscope, and/or surgical microscope prior to puncturing the round window; and monitoring the flow rate of the therapeutic fluid and/or the distribution of the therapeutic fluid throughout the inner ear using a distal tip camera, endoscope, and/or surgical microscope prior to puncture of the round window.

In some embodiments, the method includes activating the distal tip chamber prior to piercing the round window. The distal tip camera is communicatively coupled to at least one monitor that the surgeon can view during the procedure.

In some embodiments, handling the posterior tympanomeatal flap involves cutting the posterior tympanomeatal flap using a microcurette and/or drill.

In some embodiments, the procedure includes preparing and draping the ear prior to handling the posterior tympanomeatal flap; positioning the patient prior to ear preparation and draping; administering anesthesia before positioning the patient; and marking the ear before applying anesthesia.

In some embodiments, the procedure includes connecting tubing between the fluid delivery device and an upstream pump prior to handling the posterior tympanomeatal flap; sterilization of the fluid delivery device before working with the posterior tympanomeatal flap; and priming the system before working with the posterior tympanomeatal flap.

In some embodiments, the therapeutic fluid contains at least one viral gene preparation.

In some embodiments, the procedure includes removing the fluid delivery device from the inner ear after the therapeutic fluid has passed through the fluid delivery device; and applying at least one skin treatment agent to the round window membrane and/or to the base of the stapes after removal of the fluid delivery device.

In some embodiments, the procedure includes returning the posterior tympanomeatal flap to its original position after application of at least a skin treatment agent.

In some embodiments, the method includes removing bone from the junction of the bony canal and the tympanic membrane and/or the overhanging bone of the pseudomembrane after working with a posterior tympanomeatal flap.

In some embodiments, the method includes using a diamond drill and/or an otologic drill to remove bone.

In some embodiments, creating an opening in the stapes base includes creating an opening in the base of the stapes using a laser.

In some embodiments, the laser comprises an otological laser.

In some embodiments, the procedure includes applying at least one of an anesthetic and epinephrine to the patient's ear canal prior to handling the posterior tympanomeatal flap.

In some embodiments, preparing the ear includes applying at least one antiseptic to the ear.

In some embodiments, the antiseptic contains povidone-iodine, iodopovidone, betadine, vocadine and/or pyodine.

In some embodiments, the skin treatment agent contains sodium hyaluronate and/or hyaluronic acid.

In another aspect of the present invention, there is provided a method of delivering a therapeutic fluid to a portion of the inner ear (eg, using any of the devices or systems described herein), comprising: creating an opening in the base of the stapes; piercing the round window with a needle located at the distal end of the fluid delivery device; positioning the fluid delivery device at the desired insertion depth in the circular window; and passing the therapeutic fluid through the fluid delivery device into the inner ear. The therapeutic liquid contains at least one viral gene preparation.

In another aspect of the present invention, there is provided a method of delivering a therapeutic fluid to a portion of the inner ear (eg, using any of the devices or systems described herein), comprising: creating an opening in the base of the stapes; piercing the round window with a needle located at the distal end of the fluid delivery device; positioning the fluid delivery device at the desired insertion depth in the circular window; and passing the therapeutic fluid through the fluid delivery device into the inner ear. Desirable insertion depths include a depth of from about 0.7 mm to about 1.0 mm.

In some embodiments, the passage of therapeutic fluid through the device

- 4 046366 delivery of fluid to the inner ear involves the passage of therapeutic fluid at a flow rate of from about 20 μl/min to about 100 μl/min.

In some embodiments, passage of the therapeutic fluid through the fluid delivery device into the inner ear includes passage of a total volume of therapeutic fluid ranging from about 0.07 ml to about 0.11 ml.

In some embodiments, passage of the therapeutic fluid through the fluid delivery device into the inner ear includes passage of the therapeutic fluid for a time ranging from about 1 minute to about 5 minutes.

In another aspect of the present invention, there is provided a device for delivering fluid to the ear, comprising: a handle portion having a proximal end and a distal end; a telescopic support connected to the distal end of the handle portion; a needle subassembly connected to the distal end of the telescopic support, the needle subassembly comprising a curved needle; and a tube connected to the proximal end of the handle portion.

In another aspect of the present invention, there is provided a packaging system for holding a delivery device, which includes a distal end and a stop located at the distal end of the delivery device. The layout system contains: a mounting surface; and a device socket for holding the delivery device. The device socket is mounted on the mounting surface.

In another aspect of the present invention, there is provided a packaging system for holding a delivery device, the packaging system comprising: a mounting surface and a device socket for holding the delivery device. The device socket is mounted on the mounting surface.

In some embodiments, the system includes at least one pair of oppositely oriented slots located in the mounting surface.

In some embodiments, a pair of opposingly oriented slots retains a tube in fluid communication with the proximal end of the delivery device.

In some embodiments, the system includes a plurality of receptacle grooves located in the device receptacle and retaining at least one of a proximal end, a distal end, and a main portion of the delivery device.

In some embodiments, the system includes at least one mounting slot located in the mounting surface and at least one locking portion extending through the device receptacle and attached to the mounting slot.

In some embodiments, the device socket is shaped like a violin.

In some embodiments, the system includes at least one tie for securing the delivery device to the device receptacle.

In some embodiments, the pair of opposing slots includes a pair of curved ends at both ends to prevent the pair of opposing slots from damaging the mounting surface.

In some embodiments, the delivery device comprises: a device body including a distal tip and a proximal end; and a tube fluidly connected to the proximal end.

In another aspect of the present invention, there is provided a packaging system for holding a delivery device used for delivering a therapeutic fluid to the inner ear, the packaging system comprising: a mounting surface and a device socket for holding the delivery device. The device socket is attached to the mounting surface.

In some embodiments, the system comprises a polyetheretherketone tube in fluid communication with an upstream delivery device and a containment sheath disposed around the polyetheretherketone tube.

In some embodiments, the system includes a protective sheath positioned concentrically around the tube to prevent kinking of the tube.

In some embodiments, the containment shell consists of a polymeric material.

In another aspect of the present invention, a surgical procedure is provided for delivering a therapeutic fluid to a portion of the inner ear of a patient, including: administering the therapeutic fluid through a delivery device as described herein into the inner ear.

In some embodiments, the surgical procedure includes performing a transcanal tympanotomy; performing laser microstapedotomy; and administering the therapeutic fluid through a delivery device as described herein into the inner ear.

In some embodiments, the surgical procedure includes performing a transcanal tympanotomy; performing laser microstapedotomy;

administering a therapeutic fluid through a delivery device as described herein into the inner ear; applying sealant around the patient's round window and/or oval window; and lowering the patient's tympanomeatal flap to an anatomical position.

- 5 046366

In some embodiments, the surgical procedure includes performing a transcanal tympanotomy; preparing the patient's round window; performing laser microstapedotomy; preparing both the delivery device described herein and the therapeutic fluid for delivery to the inner ear; administering a therapeutic fluid through a delivery device into the inner ear; applying sealant around the patient's round window and/or oval window; and lowering the patient's tympanomeatal flap to an anatomical position.

In some embodiments, performing a laser microstapedotomy involves using a KTP otologic laser and/or a CO2 otologic laser.

In some embodiments, the therapeutic fluid comprises an AAV vector. In some embodiments, the AAV vector is an Anc80 AAV vector. In some embodiments, the AAV vector contains a coding region encoding hOTOF.

In the specification where devices, systems, procedures and/or methods are described as having, including or consisting of certain components, or where methods are described as having, including or consisting of certain steps, it is assumed that there are additional devices, systems, procedures and /or methods of the present invention that consist essentially of or consist of the specified components, and that there are methods in accordance with the present invention that consist essentially of or consist of the specified processing steps.

It should be understood that the order of steps or the order in which certain actions are performed is immaterial as long as the method remains operational. Moreover, two or more steps or actions can be performed simultaneously.

The following description is provided to illustrate and explain the invention only, and is not intended to limit the invention to the specific embodiments described.

Reference in this document to any publication, for example, in the Background Art section, does not constitute an admission that said publication is prior art with respect to any of the claims. The Background section is presented for clarity and is not intended to describe the prior art with respect to any claim.

Brief description of graphic materials

A complete and effective description of embodiments of the present invention, including the best embodiment thereof, intended for those skilled in the art, is set forth in the description with reference to the accompanying drawings, in which:

in fig. 1 is a perspective view of an inner ear fluid delivery device in accordance with aspects of embodiments of the present invention;

in fig. 2 is a side view of a curved needle subassembly in accordance with aspects of the described embodiments of the present invention;

in fig. 3 is a perspective view of an inner ear fluid delivery device in accordance with aspects of the described embodiments of the present invention;

in fig. 4 is a perspective view of a curved needle subassembly coupled to the distal end of the device, in accordance with aspects of the described embodiments of the present invention;

in fig. 5 illustrates a device coupled to a tube in accordance with aspects of the described embodiments of the present invention;

in fig. 6 illustrates a device coupled to a strain relief member in accordance with aspects of the described embodiments of the present invention;

in fig. 7 is a perspective view of a telescopic hypotube needle support, needle and stopper in accordance with aspects of the described embodiments of the present invention;

in fig. 8 is a side view of a needle in accordance with aspects of the described embodiments of the present invention;

in fig. 9 is a perspective view of a telescopic needle support with hypotubes in accordance with aspects of the described embodiments of the present invention;

in fig. 10 is a perspective view of a strain relief member in accordance with aspects of the described embodiments of the present invention;

in fig. 11 is a perspective view of a tube (or ferrule) in accordance with aspects of the described embodiments of the present invention;

in fig. 12 illustrates a device for delivering fluid to the inner ear in accordance with aspects of the described embodiments of the present invention;

in fig. 13 is a perspective view of a curved needle subassembly in accordance with aspects of the described embodiments of the present invention;

in fig. 13A is a perspective view of a curved needle subassembly in accordance with aspects of embodiments of the present invention;

in fig. 13B is a perspective view of a curved needle subassembly in accordance with aspects of embodiments of the present invention;

in fig. 13C is a side view of a device for delivering fluid to the inner ear according to

- 6 046366 with aspects of the described embodiments of the present invention;

in fig. 13D is a side view of an inner ear fluid delivery device in accordance with aspects of the described embodiments of the present invention;

in fig. 13E is a side view of an inner ear fluid delivery device in accordance with aspects of the described embodiments of the present invention;

in fig. 13F is a side view of an inner ear fluid delivery device in accordance with aspects of the described embodiments of the present invention;

in fig. 13G is a side view of an inner ear fluid delivery device in accordance with aspects of the described embodiments of the present invention;

in fig. 13H is a side view of an inner ear fluid delivery device in accordance with aspects of the described embodiments of the present invention;

in fig. 14 illustrates a complete device in a housing coupled to a tube in accordance with aspects of the described embodiments of the present invention;

in fig. 14A illustrates a complete device in an alternative arrangement coupled to a tube, in accordance with aspects of embodiments of the present invention;

in fig. 15 is a perspective view of a distal tip chamber located within a system in accordance with aspects of embodiments of the present invention;

in fig. 16 is a perspective view of a distal tip chamber located within a system in accordance with aspects of embodiments of the present invention;

in fig. 17 is a perspective view of a distal tip chamber located within a system in accordance with aspects of embodiments of the present invention;

in fig. 18 is a perspective view of a distal tip chamber located within a system in accordance with aspects of embodiments of the present invention;

in fig. 19 is a side view of a distal tip chamber, in accordance with aspects of embodiments of the present invention;

in fig. 20 is a side view of a distal tip chamber in accordance with aspects of embodiments of the present invention;

in fig. 21 is a side view of a distal tip chamber in accordance with aspects of embodiments of the present invention;

in fig. 22 is a side view of a distal tip chamber in accordance with aspects of embodiments of the present invention;

in fig. 23 is a side view of an optical fiber in accordance with aspects of embodiments of the present invention;

in fig. 23A illustrates an embodiment of a device in accordance with aspects of embodiments of the present invention;

in fig. 23B illustrates an embodiment of a device in accordance with aspects of embodiments of the present invention;

in fig. 23C illustrates an embodiment of a device in accordance with aspects of embodiments of the present invention;

in fig. 23D illustrates an embodiment of a device in accordance with aspects of embodiments of the present invention;

in fig. 23E illustrates an embodiment of a device in accordance with aspects of embodiments of the present invention;

in fig. 23F illustrates an embodiment of a device in accordance with aspects of embodiments of the present invention;

in fig. 23G illustrates an embodiment of a device in accordance with aspects of embodiments of the present invention;

in fig. 23H illustrates an embodiment of a device in accordance with aspects of embodiments of the present invention;

in fig. 24 is a side view of a delivery system in accordance with aspects of embodiments of the present invention; and in fig. 25 illustrates a method of delivering a therapeutic fluid in accordance with aspects of embodiments of the present invention.

Description of Some Embodiments of the Invention

Embodiments of the present invention will now be discussed in detail, one or more of which are illustrated in the accompanying drawings. In the detailed description, numerical and/or alphabetic notations are used to identify elements in the figures. Like or similar designations in the figures and description are used to identify like or similar parts of embodiments of the present invention.

The devices, systems and methods described herein provide potential advantages over off-the-shelf materials and other delivery systems with regard to both drug safety and efficacy. For example, the described devices and systems

- 7 046366 we have been specially developed for the intracochlear route of administration. In some embodiments, structural elements of the described device may include: maintaining sterility of the administered fluid; minimizing air bubbles entering the inner ear; the ability to accurately deliver small volumes at controlled speeds; delivery through the external auditory canal by a surgeon;

minimizing damage to the round window membrane (RWM) or inner ear, such as cochlear structures outside the RWM; minimizing leakage of injected fluid back through the RWM.

Devices, systems and methods disclosed herein also describe the potential for safe and effective delivery of fluids to the inner ear for the treatment of conditions and disorders, including, but not limited to, hearing and balance disorders or intracranial tumors, such as vestibular schwannoma, to which Such delivery of fluids to the inner ear will have a beneficial effect. As another example, by placing a vent at the base of the stapes and administering through the RWM, drugs are dispersed throughout the cochlea with minimal dilution at the site of action. The development of the described devices allows for the surgical administration of drugs through the external auditory canal in humans. The described devices can be removed from the ear after introducing a certain amount of fluid into the perilymph of the cochlea. In patients, the device can be inserted through the external auditory canal either under surgical microscopic guidance or in conjunction with an endoscope.

Devices.

In fig. 1 shows an exemplary device 10 for delivering fluid to the inner ear. The device 10 includes a knurled handle 12 and a handle distal end adhesive 14 (eg, epoxy adhesive such as Loctite 4014) that connects to a telescopic hypotube needle support 24. The knurled handle 12 (or part of the handle) may include knurled and/or grooved features to improve grip. The thickness of the knurled handle 12 (or handle portion) may be from about 5 mm to about 15 mm, or from about 5 mm to about 12 mm, or from about 6 mm to about 10 mm, or from about 6 mm to about 9 mm. , or from about 7 mm to about 8 mm. The knurled handle 12 (or part of the handle) may be hollow to allow liquid to pass through the device 10 during use. The device 10 may also include an adhesive 16 at the proximal end 18 of the knurled handle 12, a needle subassembly 26 (shown in FIG. 2) with a stop 28 (shown in FIG. 2) at the distal end 20 of the device 10, and a strain relief member 22. The strain relief member 22 may be composed of Santoprene, Pebax, polyurethane, silicone, nylon, and/or thermoplastic elastomer.

A telescopic hypotube needle support 24 surrounds and supports a curved needle 38 (shown in FIG. 2) located therein.

As shown in FIG. 1, the stopper 28 may be comprised of a thermoplastic material or a plastic polymer (e.g., an ultraviolet-curable polymer), as well as other suitable materials, and may be used to prevent the curved needle 38 from being inserted too far into the ear canal (e.g., to prevent the curved needle 38 from being inserted too far into the ear canal). into the lateral wall or other structure of the inner ear). The device 10 may also include a conical portion 23 located between the knurled handle 12 and the distal handle adhesive 14, which is connected to the telescopic hypotube needle support 24. The knurled handle 12 (or handle portion) may include a conical portion 23 at the distal end of the handle portion 12. The device 10 may also include a conduit 36 in fluid communication with the proximal end 16 of the device 10 and acting as a fluid inlet line connecting the device to upstream components (e.g., a pump, syringe, and/or upstream components, which in some embodiments implementations may be connected to a control system and/or a power supply (not shown)). In some embodiments, a curved needle 38 (shown in FIG. 2) extends from the distal end 20, through the telescopic hypotube needle support 24, through the conical portion 23, through the knurled handle 12, and through the strain relief member 22 and is fluidly coupled directly with a tube 36. In other embodiments, the curved needle 38 is in fluid connection to the hollow interior of a knurled handle (e.g., through a telescopic hypotube needle support 24), which in turn is in fluid connection at the proximal end 16 to the tube 36. In embodiments where the curved needle 38 does not extend through the entire interior of the device 10, the contact area (e.g., between overlapping nested hypotubes 42), tolerances, and/or seals between interacting components must be sufficient to prevent leakage of therapeutic fluid from the device 10 (which operates at relatively low pressure (eg, from about 1 Pascal to about 50 Pa, or from about 2 Pa to about 20 Pa, or from about 3 Pa to about 10 Pa)).

In fig. 2 is a side view of a curved needle subassembly 26 in accordance with aspects of the described embodiments of the present invention. The curved needle subassembly 26 includes a needle 38 having a curved portion 32. The curved needle subassembly 26 may also include a stop 28 coupled to the curved portion 32. The curved portion 32 includes an angled tip 34 at the distal end 20 of the ear membrane piercing device 10 (e.g. , round window membranes). The needle 38, the curved portion 32 and the angled tip 34 are hollow so that the liquid

- 8 046366 can pass through them. The angle 46 (as shown in FIG. 4) of the curved portion 32 may vary. The geometry of the restrictor 28 may be cylindrical, disk-shaped, ring-shaped, dome-shaped, and/or other suitable shape. The stopper 28 may be molded in place onto the curved portion 32. For example, the stopper 28 can be placed concentrically around the curved portion 32 using adhesives or a compression fitting. Examples of adhesives include UV curing adhesives (eg Dymax 203A-CTH-F-T), elastomeric adhesives, thermosetting adhesives (eg epoxy or polyurethane) or emulsion adhesives (eg polyvinyl acetate). Stopper 28 concentrically surrounds curved portion 32 such that the angled tip 34 is inserted into the ear to the desired insertion depth. The curved needle 38 may be formed from a straight needle by incremental molding, as well as other suitable methods.

In fig. 3 is a perspective view of an exemplary device 10 for delivering fluid to the inner ear. Tube 36 may have a length of from about 1300 mm (size 11 in FIG. 3) to about 1600 mm, or from about 1400 mm to about 1500 mm, or from about 1430 mm to about 1450 mm. The strain relief member 22 may have a length of from about 25 mm to about 30 mm (size 15 in FIG. 3), or from about 20 mm to about 35 mm. The handle 12 may have a length of about 155.4 mm (size 13 in FIG. 3), or from about 150 mm to about 160 mm, or from about 140 mm to about 170 mm. The telescopic hypotube needle support 24 may have two or more nested hypotubes, such as three stacked hypotubes 42A, 42B and 42C or four stacked hypotubes 42A, 42B, 42C and 42D (shown in FIG. 9). ). The overall length of the hypotubes 42A, 42B, 42C and tip assembly 26 (size 17 in FIG. 3) may range from about 25 mm to about 45 mm, or from about 30 mm to about 40 mm, or about 35 mm. In addition, the telescopic hypotube needle support 24 may have a length of about 36 mm, or from about 25 mm to about 45 mm, or from about 30 mm to about 40 mm. The three stacked hypotubes 42A, 42B, and 42C may have lengths of 3.5 mm, 8.0 mm, and 19.8 mm, respectively, plus or minus about 20%. The innermost inserted hypotube (or narrowest portion) of the telescopic hypotube needle support 24 may be concentrically positioned around the needle 38 (as shown in FIG. 7).

In fig. 4 is a perspective view of a curved needle subassembly 26 coupled to the distal end 20 of the device 10, in accordance with aspects of the described embodiments of the present invention. As shown in FIG. 4, the curved needle assembly 26 may include a needle 38 coupled to a curved portion 32. In other embodiments, the curved needle 38 may be a single needle (eg, a straight needle that is then curved such that it has a desired angle 46). The 38 needle may be a 33 gauge needle, or may be a gauge from about 32 to about 34, or from about 31 to 35. For finer gauges, care must be taken to ensure that the tube 36 is not kinked or damaged. The needle 38 may be attached to the handle 12 to safely and accurately insert the needle 38 into the inner ear. As shown in FIG. 4, the curved needle subassembly 26 may also include a stop 28 located around the curved portion 32. In FIG. 4 also illustrates that the curved portion 32 may include an angled tip 34 for piercing the membrane of the ear (eg, RWM). The stopper 28 may have a height 48 of about 0.5 mm, or from about 0.4 mm to about 0.6 mm, or from about 0.3 mm to about 0.7 mm. The curved portion 32 may have a length 52 of about 1.45 mm, or from about 1.35 mm to about 1.55 mm, or from about 1.2 mm to about 1.7 mm. In other embodiments, the curved portion 32 may have a length greater than 2.0 mm such that the distance between the distal end of the stop 28 and the distal end of the angled tip 34 is from about 0.5 mm to about 1.7 mm, or from about 0 .6 mm to about 1.5 mm, or from about 0.7 mm to about 1.3 mm, or from about 0.8 mm to about 1.2 mm. In fig. 4 shows that the restrictor 28 may have a cyclic, disk-shaped and/or dome-shaped geometry. One skilled in the art will appreciate that other geometric shapes may be used.

Fluid delivery to the cochlea to access the RWM in non-human primates (NHP): differs from the approach used in human patients. For example, device 10 (as shown in FIG. 1) can be advanced through the external auditory canal in human patients either under surgical microscopic guidance or in conjunction with an endoscope, which is not possible even in large NHPs (eg, baboons).

In NHP, the approach for accessing RWM is more similar to that typically used for cochlear implant procedures in patients, resulting in a slightly different angle 46 for targeting RWM. For example, angle 46 as shown in FIG. 4, may be about 55 degrees for use in human patients. Or angle 46, as shown in FIG. 4, can be around 30 degrees at NHP. In other embodiments, the angle 46 may be from about 1 degree to about 70 degrees. In other embodiments, the angle 46 may range from about 5 degrees to about 70 degrees. In other embodiments, the angle 46 may be from about 20 degrees to about 70 degrees. In other embodiments, the angle 46 may be from about 20 degrees to about 60 degrees. In other embodiments, the angle 46 may be from about 20 degrees to about 50 degrees. In other embodiments, the angle 46 may be from about 20 degrees to about 40 degrees. In other embodiments, the angle 46 may be from about 30 degrees to about 70 degrees. In other embodiments, the angle 46 may be from about 40 degrees to about 60 degrees. IN

- 9 046366 In other embodiments, the angle 46 may be about 55 degrees. In some embodiments, the angle 46 is adjustable over a range of angles during use of the device 10.

In fig. 5 shows an exemplary device 10 with a protective tube casing (or shell) 56 around the tube 36 (as shown in FIG. 6) to protect it from kinking or other damage. As shown in FIG. 5, device 10 may be placed within a device protective housing 54. The device housing 54 may be used to facilitate storage or handling of the device 10 prior to use for liquid delivery. The tube housing 56 may include one or more cylindrical portions 58 connected to the tube housing 56 to increase strength and reduce kinks and deformation of the tube housing 56 (and therefore the tube 36). The cylindrical portions 58 may also help maintain the tube housing 56 (and thus the tube 36) in a helical configuration during transport. In some embodiments, the tube housing (or containment) 56 may be composed of polyetheretherketone. In some embodiments, the tube housing 56 may be composed of a thermoplastic material.

In fig. 6 shows an exemplary device 10 coupled to a strain relief member 22. The needle 38 (shown in FIG. 1) may be attached through a telescopic hypotube needle support 24 or by such a support (shown in FIG. 1) through a handle 12 (shown in FIG. 1) to a fixed length of tubing 36 that can be attached to a syringe 60 (shown in FIG. 15) used to hold the device 10.

In fig. 7 is a perspective view of a telescoping hypotube needle support 24, a needle 38, and a stopper 28 of the device 10 in accordance with aspects of the described embodiments of the present invention. In some embodiments, the needle 38 may be concentrically located at the narrowest portion of the telescopic hypotube needle support 24.

In fig. 8 is a side view of a needle 38 in accordance with aspects of the described embodiments of the present invention. The needle 38 may include a curved portion 32. The curved portion 32 may include an angled tip 34 for piercing the membrane of the ear (eg, RWM). The 38 needle may be a 33 gauge needle. Other gauges can be used, for example gauges from about 32 to about 34 or from about 31 to about 35. For finer gauges, care must be taken that the 38 needle is not damaged. The needle 38 may be made of stainless steel (eg, 304 stainless steel). The needle 38 may also be made of any material that has properties similar to stainless steel (such as strength or other mechanical properties). For example, the needle 38 may be composed of titanium. The needle 38 may have a bend length of about 1.45 mm, or from about 1.2 mm to about 1.7 mm (as shown in Fig. 4) and an angle of about 55 degrees, or from about 40 degrees to about 70 degrees (as shown in FIG. 4). shown in FIG. 4), or from about 20 degrees to about 70 degrees, and other sub-ranges therebetween, including from about 25 degrees to about 45 degrees.

In fig. 9 is a perspective view of a telescoping hypotube needle support 24 in accordance with aspects of the described embodiments of the present invention. In some embodiments, the telescopic hypotube needle support 24 may comprise two or more stacked hypotubes, such as four stacked hypotubes 42A, 42B, 42C, and 42D (see also FIG. 3, which shows an embodiment with three hypotubes 42A, 42B and 42C inserted into each other). The needle 38 may be the narrowest part of the telescopic hypotube needle support 24. In other embodiments, the needle 38 is located at the narrowest portion 42D of the telescopic hypotube needle support 24. The telescopic hypotube needle support 24 may be made of stainless steel (eg, 304 stainless steel). The telescopic hypotube needle support 24 can also be made of any material that has properties similar to stainless steel (eg, strength or other mechanical properties). For example, the telescopic support 24 of the hypotube needle may consist of titanium. Hypotubes 42A, 42B, 42C, 42D inserted into each other can have calibers 14ХН, 20TW, 23TW and 27TW, respectively. Thus, the stacked hypotubes 42A, 42B, 42C, 42D may have outer diameters of 0.083 inch, 0.0355 inch, 0.025 inch and 0.014 inch, respectively, and inner diameters of 0.039 inch, 0.0255 inch, 0.017 inch and 0.009 inch, respectively. . In other embodiments, the interstitial hypotubes 42A, 42B, 42C, 42D may have outer diameters from about 0.2 inch to about 0.01 inch and inner diameters from about 0.08 inch to about 0.004 inch. Likewise, the stacked hypotubes 42A, 42B, 42C, 42D may have a wall thickness of from about 0.022 inches to about 0.003 inches, or from about 0.05 inches to about 0.001 inches.

As shown in FIG. 9, needle 38 may have a gauge of from about 32 to about 34, or from about 31 to about 35, with a corresponding outer diameter of about 0.01 inch to about 0.005 inch, allowing it to fit the innermost nested hypotube 42C and/or 42D depending on the number of hypotubes. Each of the interstitial hypotubes 42A, 42B, 42C, 42D may also have smooth edges between themselves and one or more adjacent hypotubes, for example, to reduce the likelihood of snagging on certain anatomical components in the external auditory canal of patients. Each of the hypotubes 42A, 42B, 42C, 42D inserted into each other can also

- 10 046366 have a radially outward flared lip at the proximal end and a radially inward flared lip at the distal end, thereby creating an obstruction to an adjacent inserted hypotube and preventing any of the stacked hypotubes 42A, 42B, 42C, 42D from being disconnected from the device 10.B In other embodiments, instead of a telescoping needle support 24, the needle support 24 may comprise a single monolithic conical element with a gradually tapering radius (e.g., tapering from the radius of the outermost hypotube 42A to the radius of the innermost hypotube 42D) instead of multiple nested hypotubes 42A, 42B, 42C and 42D. The telescopic hypotube needle support 24 may include interstitial hypotubes 42B, 42C, and 42D that extend completely through each successive wider hypotube (as shown in FIG. 9, hypotube 42B extends through the distal end of hypotube 42A).

In fig. 10 is a perspective view of a strain relief member 22 in accordance with aspects of the described embodiments of the present invention. The strain relief member 22 may include laminated projections 58A and 58B. The laminated projections 58A and 58B may comprise Pebax laminated projections. The laminated projections 58A and 58B can prevent kinking and/or deformation of the polyetheretherketone tube 36 (as shown in FIGS. 5-6) at the proximal end 18 of the knurled handle 12 (as shown in FIG. 1).

In fig. 11 is a perspective view of tube 36 in accordance with aspects of the described embodiments of the present invention. The tube 36 may be made of polyetheretherketone (PEEK). Tube 36 may also be composed of other materials, such as thermoplastic. Tube 36 may have an internal diameter of about 0.007 inches, or from about 0.005 inches to 0.01 inches. Tube 36 may have an outer diameter of about 1/32 inch, or from about 0.02 inch to about 0.05 inch. Tube 36 may be about 60 inches in length, or from about 30 inches to about 100 inches. In embodiments of device 10, when the curved needle 38 extends completely through the knurled handle 12 and is fluidly coupled directly to the tube 36, the proximal end of the curved needle 38 may be coupled to the tube 36 (e.g., when the curved needle 38 is inserted into the tube 36) using a compression fit, adhesive, ring clamp and other suitable connections.

In fig. 12 illustrates an exemplary inner ear fluid delivery device 10 comprising a telescoping hypotube needle support 24, a curved needle 38 at the distal end 20 of the device 10. As shown in FIG. 12, device 10 may include an alternative embodiment of a strain relief member 22 that may add flexibility to the interface between tube 36 and proximal end 18 of the device. An embodiment of the strain relief member 22 shown in FIG. 12 may also reduce kinking or deformation of the tube 36. The strain relief member 22 may also provide strength at the interface of the tube housing 56 (as shown in FIG. 5) with the proximal end 18 of the handle 12.

In fig. 13 is a perspective view of a curved needle subassembly 26 in accordance with aspects of the described embodiments of the present invention. The needle subassembly 26 located at the distal end 20 of the device 10 may include an angled tip 34. The stopper 28 may be located around the needle 38 such that the proximal end 33 of the stopper is adjacent to the curved portion 32 of the needle 38. The stopper 28 may include a tapered portion. 29 with a gradually increasing radius from the proximal end 33 of the stopper to the distal end 35 of the stopper. The stopper may also have one or more chamfers (eg, chamfer 31 on the distal end 35 of the stopper).

In fig. 13A is a perspective view of a curved needle subassembly 26 including an alternative stop structure 70, in accordance with aspects of the described embodiments of the present invention. An alternative limiter 70 shown in FIG. 13A may be more rounded than stopper 28 shown in FIG. 13, which may be more disc-shaped or circular. For example, the alternative stop 70 may have a maximum outer diameter that is approximately equal to its maximum length or is from about 0.75 to about 1.5 times its maximum length. In contrast, limiter 28 shown in FIG. 13 may have a maximum diameter that is about twice the maximum length or about 1.5 to about 2.5 times the maximum length. The alternative stop 70 may also include a flexible portion 72 that is rounded or curved (ie, convex) toward the distal end of the curved needle subassembly 26. The alternative stop 70 may also include a rigid portion 74 that is located closer to the flexible portion 72. The rigid portion 74 may have an outer diameter that is smaller than that of the flexible portion 72.

In fig. 13B is a perspective view of a curved needle subassembly 26 including an alternative stop structure 71 in accordance with the described embodiments of the present invention. An alternative limiter 71 in FIG. 13B includes a conical portion 77 that gradually tapers from the needle toward the outer circumference 79 of the stop. The alternative stop 71 may also include an edge-shaped portion 75 that extends slightly toward the distal tip of the needle 34. The alternative stop 71 may also have a smaller aspect ratio (for example, compared to the stops shown in FIGS. 13 and 13A) so that the largest

- 11 046366 the diameter of the stopper 71 (for example, measured along the outer circumference 79) is about 10 times the minimum thickness of the stopper 71. In other embodiments, the largest diameter of the stopper 71 may be from about 7 to about 12 times the minimum thickness of the stopper 71 or from about 5 to about 15 times the minimum limiter thickness 71.

In fig. 13C illustrates an embodiment of the distal end 20 of the device 10 (including the needle tip 34) in accordance with aspects of the embodiments of the present invention. In the embodiment shown in FIG. 13C, the device 10 includes a stopper attachment slot 200 located within the device 10 at the distal end 20. The stopper attachment slot 200 may be used to facilitate attachment of the stopper 28, 70, 71 (shown in FIGS. 2, 4, 13, 13A, 13B and 15-18) around the needle 38 at the distal end 20.

In fig. 13D is an enlarged view of a stopper mounting slot 200 in accordance with aspects of embodiments of the present invention. The restrictor attachment slot 200 may include a first inclined portion 202 (e.g., adjacent to a distal end 20 of the restrictor attachment slot 200), a second inclined portion 204 (e.g., adjacent to a proximal end 18 of the restrictor attachment slot 200), and a recessed portion 206 (or a flat portion 206) located axially between the first and second inclined portions 202, 204 (thereby forming a stopper mounting groove 200). The recessed portion 206 has a smaller diameter than the rest of the needle 38. Each of the first and second inclined portions 202, 204 may extend linearly from the outer circumference of the needle 38 to the recessed portion 206 and/or may be rounded (thereby forming one or more fillets) .

In fig. 13E is an enlarged view of the transition between the device handle 12 and the telescoping hypotubes 24 in accordance with aspects of embodiments of the present invention. In the embodiment shown in FIG. 13E, the device may include a protruding connection 210 (or reinforcement, such as a ring reinforcement) that reinforces the transition between the handle 12 of the device and the telescopic hypotubes 24. As such, the protruding connection 210 (or reinforcement) may be located at the interface between the handle portion 12 and telescopic hypotubes 24 (or support). The protruding connection 210 may have a larger outer diameter than the outer diameter of the handle part 12, so that the portion of the protruding connection 210 is located around the handle part 12. The protruding connection 210 may also include an inner diameter that closely fits the outer diameter of the thickest member of the plurality of telescoping hypotubes 24.

In fig. 13F illustrates an embodiment of an apparatus 10 in accordance with aspects of the embodiments of the present invention. In the example shown in FIG. 13F, the device 10 includes a machined boss 212 integrated into the proximal end 18 of the handle 12 of the device. The machined boss 212 may be used in conjunction with the strain relief members 22 (shown in FIGS. 1, 3, 12 and 13H) to prevent the strain relief members 22 from axially detaching from the handle 12 of the device.

In fig. 13G is an enlarged view of a machined boss 212 in accordance with aspects of embodiments of the present invention. The machined boss 212 may include a first inclined portion 214 (e.g., at the proximal end 18 of the handle 12 of the device), a second inclined portion 216, and a plateau portion located between the first and second inclined portions 214, 216.

In fig. 13H is an enlarged view of strain relief members 22 in accordance with aspects of embodiments of the present invention. (The device shown in Fig. 13H is presented in the opposite orientation to that shown in Figs. 13F and 13G). The polyetheretherketone tubes 36 may be glued (eg, using epoxy adhesive 220) or otherwise connected to the handle 12 of the device. The strain relief members 22 may be positioned around the polyetheretherketone tube 36, which itself may be positioned around the needle 38 to prevent kinking (and/or other damage) to the needle 38. In addition, the machined boss 212 helps prevent the strain relief members 22 from becoming dislodged or detached from handles 12 devices. In some embodiments, the strain relief members may be composed of molded santoprene as well as other suitable materials. In some embodiments, in order for the PEEK tubing 36 to surround the needle 38, the PEEK tubing 36 may be split around the needle 38. A heat shrink sleeve (not shown) may be placed at the joint between the PEEK tubing 36 and the needle 38. The junction may then be exposed to heat. After exposure to heat, the joint can be remelted or reshaped so that it has a smooth outer profile.

Layout system.

In fig. 14 illustrates an arrangement 55 comprising a device 10 housed in a device housing 54 and coupled to a tube housing 56. For example, arrangement 55 may include a sterile device 10 for delivering fluid to the round window membrane through the external auditory canal. Arrange

- 12 046366 product 10 can also be a disposable product. In this embodiment, the device is disposed of appropriately (eg, in a biohazard container). In some embodiments, the assembly 55, tube housing 56, device housing 54, device 10, and components thereof are all made of materials that are durable enough to withstand gamma sterilization (e.g., gamma irradiation, which uses cobalt 60 radiation to kill microorganisms and microbes). In some embodiments, the assembly 55, tube housing 56, device housing 54, device 10, and components thereof are made of materials that are all sufficiently temperature stable to withstand steam sterilization.

In fig. 14A is a top perspective view of device 10 nested within an alternative arrangement 100 (or packaging system 100), in accordance with aspects of embodiments of the present invention. The assembly (or packaging system) 100 provides safe and sterile transportation and/or shipping of the device 10. The assembly 100 may include a mounting surface 80 and a device socket 90 located on the mounting surface 80. The mounting surface 80 may consist of cardboard, reinforced cardboard, or polymeric materials. The mounting surface 80 may also consist of cardboard or reinforced paperboard with a polymer coating. The device receptacle 90 may be composed of materials similar to the mounting surface 80. The device receptacle 90 may protrude from the plane of the mounting surface 80. The mounting surface 80 may include multiple pairs of opposingly oriented slots 114. The slots may be cut into the mounting surface 80 to help retain PEEK tubing 36 in place, thereby preventing kinks, twisting, tearing, and/or other damage to PEEK tubing 36 (and the metal tubing therein). Each slot of each pair of opposing slots 114 may include a pair of curved ends 118 at each end to prevent the slots 114 from causing tears and/or tears in the mounting surface 80 due to external forces acting on the opposing slots 114. The opposing slots 114 prevent kink and/or underbend of the polyetheretherketone tube 36 (and the metal tubes therein) because the slots are located on both sides (i.e., radially inward and outward) of the polyetheretherketone tube 36 in the rolled state, thereby maintaining the desired radius of the rolled tube 36. B the embodiment shown in FIG. 14A, the mounting surface 80 includes a total of 5 pairs of opposing slots 114. However, in other embodiments, the mounting surface 80 may include a different number of pairs of opposing slots 114, including optionally 1, 2, 3, 4, 6, 7, 8 ,9, 10 And/or more than 10.

As shown in FIG. 14A, an alternative arrangement (or arrangement system) 100 may include at least one pair of opposingly oriented sliders 116 positioned adjacent the luer lock 61 to support the luer lock 61 and prevent damage thereto. The device receptacle 90 may be used to support the device 10 and may include multiple pairs of receptacle grooves 84, 86, 88, 92, 94, 96 that prevent the device 10 from moving laterally or longitudinally within the device receptacle 90. For example, a pair of socket grooves 84 are located to retain the strain relief member 22 (shown in FIGS. 1 and 12), pairs of socket grooves 86, 88 and 92 are located at the proximal end of the main body of the device 10, and pairs 94 and 96 of socket grooves are located in the direction the distal end of the device 10. The device receptacle 90 may have a first contour portion 114 near the middle portion of the main body of the device 10 for receiving a semi-flexible tie 76 that is used to secure the device to the device receptacle 90. The device socket 90 may also have first and second tie holes 78, 82 to allow the tie 76 to pass under the device socket 90, thereby around the bottom of the device socket 90 to hold the device socket 90 and the device 10 tightly together. . The device receptacle 90 may also have a tip opening 104 at the distal end to protect the tip and subassembly of the curved needle of the device 10. Thus, the device tip 10 may be located in the tip opening 104, thereby minimizing the risk of damage due to contact of the tip with any -or structures.

As shown in FIG. 14A, the device receptacle 90 may include a second contour portion 102 at the distal end for housing the tip of the device 10 and the tip opening 104. The device receptacle 90 gradually expands from the centerline of the device (i.e., from the center of the pairs of receptacle grooves 84, 86, 8, 92, 94, and 96) on each of the first and second contour portions 114, 102 such that the device receptacle 90 the device forms a violin shape, including a thinned portion 120 positioned longitudinally between the first and second contour portions 114, 102. The walls of the device socket 90 protruding from the plane of the mounting surface 80 may protrude gradually, for example, as illustrated by the cone 98, which gradually transitions from a raised projection (or wall) on the thinned portion 120 down to the plane of the mounting surface 80. The layout (or layout system) 100 in the embodiment shown in FIG. 14A may also include a tube housing (or protective shell) 56 (shown in FIGS. 5 and 14). The tube housing (or containment) 56 may be positioned concentrically around the polyetheretherketone tube 36 to help

- 13 046366 protects the polyetheretherketone tube 36 and prevents it from kinking, bending and/or other damage. The tube housing 56 (or protective sheath) may be placed around the PEEK tube 36 (e.g., prior to shipment or transportation of the device 10 and/or system 100) and may be removed by disconnecting the luer lock 61 from the PEEK tube 36 and/or prior to the luer lock connection. 61 with a polyetheretherketone tube 36. The tube casing (or containment) 56 may be composed of any suitable material, for example, polymers such as polyetheretherketone, composite materials, metallic materials, as well as other suitable materials.

As shown in FIG. 14A, the assembly (or assembly system) 100 may have one or more locking elements, including a first locking portion 106 adjacent the proximal end of the device 10 and the device receptacle 90, and a second locking portion 108 adjacent the distal end of the device 10. the portion 108 may overlap the thinned portion 120 of the device socket 90. Each of the first and second locking portions 106, 108 extends from one side of the mounting surface 80 and through the device slot 90 (ie, after placing the device 10 in the device slot 90) to a mounting surface 80 on the other side of the device slot 90. The first and second locking portions 106, 108 may be attached to the first and second fastening slots 110, 112, with the first fastening slot 110 located within the mounting surface 80 at the proximal end of the device socket 90 and the second fastening slot 112 located at the distal end of the device socket 90. devices. The first locking portion 106 cooperates with and is attached to the first fastening slot 110, and the second locking portion 108 interacts with and is attached to the second fastening slot 112. The device socket 90 may be coupled to the mounting surface 80 by any suitable mechanisms, including epoxy resin, fusion, adhesive, adhesive, and other suitable means. Additionally, in some embodiments, the device socket 90 may be formed using 3D printing (eg, fused deposition modeling (FDM), stereolithography (SLA), as well as other methods). In some embodiments, the assembly 100, device socket 90, mounting surface 80, and components thereof are made of materials (e.g., polymers, thermoset plastics, thermoplastics, composite materials, and other materials) sufficiently temperature stable to withstand steam sterilization, gamma-ray sterilization, irradiation (which uses cobalt 60 irradiation to kill microorganisms and germs) and other sterilization methods.

Systems.

The system of the present invention may include at least one distal tip camera for visualizing and/or monitoring fluid delivery to a target site (eg, the outer, middle and/or inner ear). In some embodiments, the distal tip camera may be operatively coupled to the device 10, and in other embodiments, the distal tip camera may be installed as part of the device 10 (ie, an all-in-one device). The distal tip chamber may contain at least one of a charge coupled device (CCD) and a complementary metal oxide semiconductor (CMOS). The distal tip camera may include at least one image sensor (e.g., a lens) for receiving, transmitting, and/or converting a signal (e.g., an analog or digital signal) from a target location (e.g., the outer, middle, and/or inner ear). In some embodiments, the distal tip camera may further comprise at least one processor (e.g., a video processor or a distal tip camera processor) for image processing and/or control of the distal tip camera, while in other embodiments, the processor may be located separately from the distal tip camera . The distal tip camera and/or image sensor may have a cuboid shape, a plate shape, an oblate cube shape, a cylindrical shape, and combinations thereof.

In fig. 15 is a perspective view of the distal tip chamber 1004 located above the stopper 28 in the system 1000 in accordance with aspects of embodiments of the present invention. The stopper 28 may be attached to the outer surface 1020 of the curved portion 32 of the needle 38. The distal tip chamber 1004 may be operably coupled to the wire 1002. In some embodiments, the distal tip camera 1004 may be located on the front surface 1006 of the stopper 28. In some embodiments, the stopper 28 may be located on the front surface 1006 of the stopper 28. The distal tip 1004 may be integrated into the front surface 1006 of the stopper 28. The front surface 1006 may face a target location (eg, the outer, middle, and/or inner ear). In some embodiments, the distal tip chamber 1004 may be located on the side surface 1008 of the stopper 28 (not shown).

In fig. 16 is a perspective view of a distal tip chamber 1004 located in a cavity 1010 within a stopper 28 in a system 1000 in accordance with aspects of embodiments of the present invention. The stop 28 may be attached to the outer surface 1020 of the curved portion 32 of the needle 38. The distal tip chamber 1004 may be operably coupled to the wire 1002. The cavity 1010 may be created by cutting out a portion (e.g., up to 30%) of the stop.

- 14 046366 body 28. In some embodiments, the cavity 1010 may be located near or adjacent to the outer surface 1020 of the device 10.

In fig. 17 is a perspective view of a distal tip chamber 1004 located behind the stopper 28 in the system 1000, in accordance with aspects of embodiments of the present invention. The stopper 28 may be attached to the outer surface 1020 of the curved portion 32 of the needle 38. The distal tip chamber 1004 may be operably coupled to the wire 1002. In some embodiments, the distal tip camera 1004 may be located on the rear surface 1012 of the stopper 28 (as shown in FIG. 17), and in some embodiments, the distal tip chamber 1004 may be located behind the rear surface 1012 of the stopper 28 (as shown in FIGS. 23D and 23F).

In fig. 18 is a perspective view of a distal tip chamber 1004 located in the system 1000, in accordance with aspects of embodiments of the present invention. The stopper 28 may be attached to the outer surface 1020 of the curved portion 32 of the needle 38. The distal tip chamber 1004 may be operatively coupled to the wire 1002. The distal tip chamber 1004 may contain or be operably coupled to a light source 1022 (eg, an LED light source). In some embodiments, the distal tip camera 1004 and/or the light source 1022 may be located above the stopper 28. In some embodiments, the distal tip camera 1004 and/or the light source 1022 may be located on or integrated into the stopper 28 (not shown). In some embodiments, the distal tip camera 1004 and/or the light source 1022 may be located behind the stopper 28 (not shown).

As shown in FIG. 15-18, the distal tip chamber 1004 may be operatively coupled to the outer surface 1020 of the curved portion 32 of the needle 38. In one or more embodiments, the stopper 28 may be transparent and/or include a transparent portion 1014 so that the distal tip camera 1004 can see through the stopper. 28 to monitor and/or visualize a target location (eg, outer, middle and/or inner ear). The transparent portion 1014 may contain at least a transparent material (eg, plastic, thermoplastic, polymers, and/or other suitable materials). In some embodiments, the transparent portion 1014 may be part of the cavity 1010. In one or more embodiments, about 30% (or about 20% to about 40%) of the stopper 28 may be removed so that the distal tip chamber 1004 can be integrated and /or included in the curved needle subassembly 26 (Fig. 2 and Fig. 13).

As shown in FIG. 15-18, the distal tip camera 1004 may be operably coupled via a wire 1002 to at least one of a power supply to provide power to and/or communication with the distal tip camera 1004. In some embodiments, portions of wire 1002 may be operatively attached to the outer surface 1020 of needle 38. In some embodiments, portions of wire 1002 may be operatively embedded in a portion of device 10. For example, in one or more embodiments, wire 1002 may be located on the outside of curved needle 38 and a telescopic hypotube needle support 24, as well as at least partially within the handle 12 of the device 10. In some embodiments, the wire 1002 may have a diameter of up to 10 mm. In some embodiments, wire 1002 may have a diameter of up to 5 mm. In some embodiments, wire 1002 may have a diameter of up to 3 mm. In some embodiments, wire 1002 may have a diameter of up to 1 mm. In some embodiments, wire 1002 may have a diameter of up to 0.8 mm. In some embodiments, wire 1002 may have a diameter of up to 0.6 mm. In some embodiments, wire 1002 may have a diameter of up to 0.4 mm. In some embodiments, wire 1002 may have a diameter of up to 0.2 mm. In some embodiments, wire 1002 may have a diameter of up to 0.1 mm. In some embodiments, wire 1002 may have a diameter of up to 0.05 mm.

In fig. 19 is a side view of a distal tip chamber 1004A in accordance with aspects of embodiments of the present invention. The distal tip camera 1004A may include an image sensor 1102A for receiving, transmitting, and/or converting a signal (eg, an analog or digital signal) from a target location (eg, the outer, middle, and/or inner ear) into an image. The image sensor 1102A may have a cuboidal shape.

In fig. 20 is a side view of a distal tip chamber 1004B in accordance with aspects of embodiments of the present invention. The distal tip camera 1004B may include a distal tip camera module 1104A, which includes an image sensor 1102A, a processor (e.g., a video processor or a processor built into the distal tip camera 1004), and/or other elements (e.g., a driver and/or software packages) for the distal tip camera 1004B for the purpose of accessing, operating, and/or processing images (eg, images from image sensor 1102A). In some embodiments, the distal tip camera module 1104A may have an arrangement size of up to 0.7 mm x 0.7 mm with a z height of up to 1.2 mm. In some embodiments, the distal tip camera module 1104A may have a layout size

- 15 046366 up to 1.1 mm x 1.1 mm with z height up to 2.4 mm. In some embodiments, the distal tip camera module 1104A may have an arrangement size of up to 1.5 mm x 1.5 mm with a z height of up to 3 mm. In some embodiments, the distal tip camera module 1104A may have an arrangement size of up to 2 mm x 2 mm with a z height of up to 5 mm.

As shown in FIG. 19-20, image sensor 1102A can have dimensions up to 10 mm x 10 mm, 5 mm x 5 mm, 2 mm x 2 mm, 1.8 mm x 1.8 mm, 1.6 mm x 1.6 mm, 1.4 mm x 1.4 mm, 1.2 mmx 1.2 mm, 1 mmx1 mm, 0.8 mmx0.8 mm, 0.6 mmx0.6 mm, 0.4 mmx0.4 mm, 0.2 mmx0.2 mm, 0.1 mmx0.1 mm or 0.05 mmx0.05 mm with heights up to 100, 20 10, 5, 3, 2, 1, 0.8, 0.6, 0.4, 0.2 or 0.1 mm.

As shown in FIG. 19-20, image sensor 1102A may include an imaging array capable of capturing video at a resolution of at least 10x10, 50x50, 100x100, 200x200, 400x400, 500x500, or 1000x1000 pixels at a frame rate of at least 5, 10, 20, 30, 50 , 100, 500 or 1000 frames per second.

As shown in FIG. 19-20, the image sensor 1102A may have an image area of no more than 10 mm x 10 mm, 5 mm x 5 mm, 2 mm x 2 mm, 1.8 mm x 1.8 mm, 1.6 mm x 1.6 mm, 1.4 mm x 1.4 mm, 1.2 mmx1.2 mm, 1 mmx1 mm, 0.8 mmx0.8 mm, 0.6 mmx0.6 mm, 0.4 mmx0.4 mm, 0.2 mmx0.2 mm, 0.1 mmx0 .1 mm or 0.05 mmx0.05 mm. The image sensor 1102A may have a low light sensitivity of up to 10, 100, 500, 800, 1000, 1200, 1500, 2000, 3000, or 10000 mV/lux-sec.

As shown in FIG. 19-20, image sensor 1102A can have an optical format of up to 10, 5, 2, 1.8, 1.6, 1.4, 1.2, 1, 0.8, 0.6, 0.4, 0 ,2, 0.1 or 0.05 mm and pixel sizes up to 10, 8, 6, 4, 3, 2.5, 2.2, 2, 1.8, 1.6, 1.4, 1, 2 or 1 µm.

In fig. 21 is a side view of a distal tip chamber 1004C in accordance with aspects of embodiments of the present invention. The distal tip camera 1004C may include an image sensor 1102C for receiving, transmitting, and/or converting a signal (eg, an analog or digital signal) from a target location (eg, the outer, middle, and/or inner ear) into an image. The image sensor 1102C shown in FIG. 21 may have the shape of a plate or a cylinder.

In fig. 22 is a side view of a distal tip chamber 1004D in accordance with aspects of embodiments of the present invention. The distal tip camera 1004D may include a distal tip camera module 1104C, which includes an image sensor 1102C, a processor (e.g., a video processor or a distal tip camera processor), and/or other elements (e.g., a driver and/or software packages) for the distal tip camera 1004D for the purpose of accessing, operating and/or processing images (eg, images from image sensor 1102C).

As shown in FIG. 21-22, the image sensor 1102C may include an outer diameter of up to 10 mm, 5 mm, 2 mm, 1.8 mm, 1.6 mm, 1.4 mm, 1.2 mm, 1 mm, 0.8 mm, 0.6 mm, 0.4 mm, 0.2 mm, 0.1 mm or 0.05 mm with lengths up to 100, 20, 10, 5, 3, 2, 1, 0.8, 0.6, 0.4, 0.2 or 0.1 mm.

As shown in FIG. 21-22, the image sensor 1102C may include an imaging matrix configured to capture video at a resolution of at least 10x10, 50x50, 100x100, 200x200, 400x400, 500x500, or 1000x1000 pixels at a frame rate of at least 5, 10, 20, 30 , 50, 100, 500 or 1000 fps.

As shown in FIG. 21-22, the image sensor 1102A may include an image area of no more than 10 mm x 10 mm, 5 mm x 5 mm, 2 mm x 2 mm, 1.8 mm x 1.8 mm, 1.6 mm x 1.6 mm, 1.4 mm x 1.4 mm, 1.2 mmx1.2 mm, 1 mmx1 mm, 0.8 mmx0.8 mm, 0.6 mmx0.6 mm, 0.5 mmx0.5 mm, 0.4 mmx0.4 mm, 0.2 mmx0 .2 mm, 0.1 mmx0.1 mm or 0.05 mmx0.05 mm. The image sensor 1102A may have a low light sensitivity of up to 10, 100, 500, 800, 1000, 1200, 1500, 2000, 3000, or 10000 mV/lux-sec.

As shown in FIG. 19-22, 1102A sensors, C images can be collected using integrated circuit packages (eg, packages on a chip (CSP)) that have an area of up to 0.1 mm x 0.1 mm, 0.3 mm x 0.3 mm, 0 .6 mmx0.6 mm, 0.9 mmx0.9 mm, 1.2 mmx1.2 mm or 2 mmx2 mm.

As shown in FIG. 19-22, distal tip chambers 1004A-D may include a gate (eg, a sequential gate) (not shown). The 1004A-D distal tip cameras can operate at temperatures from -20°C to 70°C. The distal tip cameras 1004A-D may have a field of view of at least 90, 100, 120, 130, or 150 degrees. In some embodiments, the distal tip cameras 1004A-D may include at least one internal light source, and in some embodiments, the distal tip cameras 1004A-D may be externally coupled to at least one light source (eg, LED light source 1022).

In fig. 23 is a side view of an optical fiber 1302 in accordance with aspects of embodiments of the present invention. In the present description, the optical fiber 1302 may be used as a light source, an image sensor 1004E, or both. Optical fiber 1302 may comprise at least one optical fiber. In some embodiments, the optical fiber 1302 may have a diameter of up to 5 mm and a length of up to 10 m. In some embodiments, the optical fiber 1302 may have a diameter of up to 1 mm and a length of up to 10 m. In some embodiments, the optical fiber 1302 may have a diameter

- 16 046366 up to 0.5 mm and a length up to 10 m. In some embodiments, the optical fiber 1302 can have a diameter up to 0.4 mm and a length up to 10 m. In some embodiments, the optical fiber 1302 can have a diameter up to up to 0.3 mm in diameter and up to 1 m in length. In some embodiments, optical fiber 1302 may have a diameter of up to 0.2 mm and up to 1 m in length. In some embodiments, optical fiber 1014 can have a diameter up to 0.1 m in diameter. mm and length up to 0.1 m.

As shown in FIG. 19-23, the distal tip camera 1004A-E and/or the optical fiber 1302 may contain or operate with a processor (eg, a video processor) (not shown) with dimensions down to 0.01 mm x 0.01 mm x 0.01 mm; 0.1 mmx0.1 mmx0.1 mm; 0.2 mmx0.1 mmx0.2 mm; 0.3 mmx0.1 mmx0.4 mm; 0.3 mmx0.3 mmx0.4 mm; 0.4 mmx0.4 mmx0.4 mm or 1 mmx1 mmx1 mm. In some embodiments, the image sensors 1102A, C may be no larger than or no longer than the distal tip camera modules 1104A, C.

As shown in FIG. 15-23, distal tip chamber 1004 may comprise at least one of distal tip chambers 1004A-D, optical fiber 1302, and/or a combination thereof. The image sensor 1102 may comprise at least one of image sensors 1102A, C, optical fiber 1302, and/or a combination thereof.

As shown in FIG. 15-23, in one or more embodiments, the distal tip camera 1004 may conveniently include biocompatible, lead-free, autofocus, disposable, reusable, low noise, low power, low heat, and/or low noise characteristics. The distal tip camera 1004 may produce color, gray images, and/or a combination thereof.

As shown in FIG. 15-23, in some embodiments, the distal tip chamber 1004 may have a working distance of up to 100 mm. In some embodiments, the distal tip camera 1004 may have a working distance of up to 50 mm. In some embodiments, the distal tip chamber 1004 may include a working distance of up to 20 mm. In some embodiments, the distal tip chamber 1004 may include a working distance of up to 10 mm. In some embodiments, the distal tip camera 1004 may include a working distance of up to 5 mm.

In fig. 23A, 23B, and 23C illustrate device 10 including a distal tip chamber 1004 integrated into stopper 28. FIG. 23A shows the device 10 with a portion of the tip circled A, indicating the detail area in FIG. 23B and 23C. In fig. 23B is a perspective view of a portion of the tip, and FIG. 23C is a side view of a portion of the tip. In the embodiment of FIG. 23A, 23B, and 23C, device 10 may include a lens or sensor 1102 and a camera assembly (eg, distal tip camera 1004) integrated into stopper 28. In some embodiments, stopper 28 may be molded around distal tip camera 1004. The distal tip chamber 1004 may also be attached to the stopper 28 using adhesive, epoxy, and/or other suitable mechanisms. Wire 1002 provides power and communication to distal tip camera 1004. In some embodiments, wire 102 may be sized such that it extends or is routed between two telescoping hypotubes (eg, between two members 42A, 42B, 42C, or 42D in FIG. 9).

In fig. 23D, 23E and 23F show device 10 including a distal tip chamber 1004 axially separated from stopper 28 (eg, behind stopper 28). In the embodiments shown in FIGS. 23D, 23E, and 23F, device 10 may include a distal tip camera 1004 and lens 1102 that are mounted on one of the telescopic hypotubes (e.g., member 42A, 42B, 42C, or 42D in FIG. 9) and may be positioned and/or curved so in a way that they capture a representative view at the tip of the needle. The distal tip chamber 1004 may be attached to the hypotube using adhesive, epoxy, welding, and/or other suitable mechanisms. In fig. 23E shows a distal tip camera 1004 and a lens or sensor 1102 in an oblique configuration 1103.

In fig. 23G and 23H show a device 10 including a distal tip chamber 1004, a lens 1102, and a wire 1002 mounted adjacent one of the telescoping hypotubes (eg, members 42A, 42B, 42C, or 42D of FIG. 9). The distal tip chamber 1004 may be attached to the hypotube using adhesive, epoxy, welding, and/or other suitable mechanisms. In the embodiments shown in FIGS. 23G and 23H (and FIGS. 23A-23F), device 10 may include a camera module housing 1106 externally enclosing a distal tip camera 1004, a lens 1102, and a wire 1002.

As shown in FIG. 15-23 (including FIGS. 23A-23H), in some embodiments, the device (including the camera) has an overall effective diameter of less than about 10 mm, or from about 1 mm to about 10 mm, or from about 1 mm to about 8 mm, or from about 1 mm to about 5 mm, or from about 1 mm to about 4 mm, or from about 2 mm to about 4 mm, or from about 1 mm to about 3 mm, or from about 1.5 mm up to about 3 mm, or from about 1 mm to about 2.5 mm, and/or less than about 3 mm.

- 17 046366

In fig. 24 illustrates a system 2400 comprising a device 10 in accordance with aspects of the described embodiments of the present invention. System 2400 may also include a distal tip camera 1004, a wire 1002, a light source 1022 as described herein, and/or a monitor 2402. The monitor 2402 may be operably coupled to the distal tip camera 1004. In some embodiments, the system 2400 may further comprise one or more syringes 60 for administering liquids, one or more pumps 2408 in fluid communication with the syringe(s) or tubing 36 (shown in FIGS. 3-5), a power supply 2410 , sterilization equipment, sharps containers (eg, biohazard container), drills 2404 (eg, otologic drill and/or diamond drill), and/or lasers 2406 (eg, KTP or CO ₂ otologic laser) (not shown ). In some embodiments, the system 2400 may include microscopes, endoscopes, and/or fiberscopes (not shown) (for example, if the system 2400 does not have a distal tip camera 1004). Syringe 60 may contain a Luer-Lok™ syringe and have a volume from about 1 ml to about 100 ml, including various volumes and spacing therebetween, including about 2 ml, about 2.5 ml, about 5 ml, about 10 ml, about 20 ml, about 30 ml, about 50 ml and/or about 60 ml. Syringe 60 may be graduated from about 0.002 ml to about 2.0 ml, or from about 0.005 ml to about 1.0 ml, or from about 0.01 ml to about 0.5 ml, or from about 0.05 ml to about 0.2 ml, or about 0.1 ml. The syringe 60 preferably and/or additionally complies with ISO 13485, as well as other applicable safety and quality standards.

As shown in FIG. 24, pump 2408 is capable of producing the desired flow and pressure conditions in accordance with the present invention and may be integrated with the syringe 60. Pump 2408 may include a Medfusion® 3500 and/or Harvard Apparatus 70-2000 syringe pump and/or may also include other designs, configuration and arrangement (including pumps manufactured by other component manufacturers), provided that the pump 2408 is capable of producing the desired flow and pressure conditions in accordance with the present invention. The pump 2408 can accommodate a variety of syringe volumes, including from about 1 ml to about 100 ml. Pump 2408 can also provide various flow rates, including from about 1 ml/hour to about 50 ml/hour, or from about 2 ml/hour to about 40 ml/hour, or from about 3 ml/hour to about 25 ml/hour. hour, or from about 4 ml/hour to about 20 ml/hour, or from about 5 ml/hour to about 15 ml/hour, or from about 8 ml/hour to about 12 ml/hour, or from about 0.5 ml/hour to 15 ml/hour, or from about 1 ml/hour to 12 ml/hour, or from about 2 ml/hour to 10 ml/hour, or from about 2.5 ml/hour to 8 ml/hour, or from about 3 ml/hour to 7 ml/hour, or from about 4 ml/hour to 6 ml/hour. Pump 2408 may have an operating relative or gauge pressure ranging from about 0 psig. inch to about 50 psi. inch and can withstand back pressure ranging from about -300 mmHg. Art. up to about +900 mm Hg. st, while simultaneously ensuring the required flow rate in the device.

As shown in FIG. 24, device 10 may be coupled to syringe 60 via a Luer lock 61 (e.g., a Luer-Lok™ syringe that may be integrated with syringe 60 and/or pump 2408) to minimize air entrapment during fluid delivery to the ear and provide an appropriate connection with tube 36 (for example, as shown in Fig. 1, 3, 6 and/or 12). The 61 Luer (or Luer Fitting) may contain a custom bushing insert that is used to facilitate the removal of air from the system. A custom bushing can be molded from silicone (or other suitable materials) and can be inserted into the inside of the 61 Luer lock (or fitting). The custom sleeve may have a generally cylindrical shape with a central hole (or lumen) through which the end of the polyetheretherketone tube 36 can be passed. The central hole (or lumen) may have a conical entrance. The custom bushing helps occupy the dead space inside the luer 61 (or fitting) so that the amount of air inside the luer 61 (or fitting) is minimized. The Luer lock 61 may include Luer lock and/or Luer slip connectors and may also include a sliding tip. In addition, the luer lock 61 may have a male thread coupled to the syringe 60 that engages a female thread coupled to the needle 38, as well as other suitable seal connector and/or connection configurations. The syringe 60 may be used to administer liquids, such as a therapeutic liquid containing a drug, which may be a small molecule or a biological drug, such as an antibody or viral gene preparation. The syringe 60 may be configured separately from other components of the device to provide device preparation. Syringe 60 can be sterilized. Device preparation may occur outside the operating room (eg, in a pharmacy). Device preparation can occur inside the operating room. Preparation of the device can be carried out using a sterilization field and/or sterilization equipment. By adding a distal tip camera 1004 to device 10, the surgeon can see around corners, thereby avoiding the need to remove obstructions such as overhanging bone. Additionally, the use of a delivery device (or microcatheter) 10 with an integrated distal tip camera 1004 allows the surgeon to operate with a single instrument to puncture the round window, deliver therapeutic fluid, and visualize the outer, middle, and/or inner ear.

- 18 046366

Ways.

In fig. 25 depicts a method 2500 that can be used to install device 10 (or microcatheter) and deliver fluid, such as a therapeutic fluid, to the inner ear, in accordance with aspects of embodiments of the present invention. In some embodiments, the present disclosure describes a delivery approach that utilizes a minimally invasive, well-accepted surgical technique to access the middle ear and/or inner ear through the external auditory canal. The method includes opening one of the physical barriers between the middle and inner ear at the oval window and then using a delivery device 10 (or microcatheter) to deliver a therapeutic fluid (for example, including one or more biological drugs, such as a viral gene drug for the treatment of hearing loss) with controlled flow rate and in a fixed volume through a round window membrane. In fig. 25 generally describes the surgical procedure as applied to humans. However, similar techniques and procedures are also applicable to mice, rodents and non-human primates, as described in the following paragraphs.

Delivery device 10 may be placed in a sterile operating room field, and the end of tubing 36 may be withdrawn from the sterile field and connected to a syringe 60 that has been filled with therapeutic fluid and installed in a pump. After appropriate priming of the system 2400 to remove air, the needle 38 can then be passed through the middle ear under visualization (surgical microscope, endoscope, and/or distal tip camera 1004). A 38 gauge needle (or microneedle) can be used to pierce the RWM. The needle 38 can be inserted until the stopper 28 makes contact with the RWM. The device 10 can then be held in this position while the therapeutic fluid is delivered at a controlled flow rate into the inner ear. Once delivery is complete, device 10 can be removed. The device 10 may be designed as a disposable product. In other embodiments, the device 10 may be configured as a reusable sterilizable article, for example, with a replaceable and/or sterilizable needle subassembly 26. The disposable devices 10 may be appropriately disposed of (eg, in a biohazard container) after completion of administration.

As shown in FIG. 25, the surgical procedure or method 2500 of introducing a therapeutic fluid into the patient's inner ear may include, at 2502, marking the ear to be treated with a permanent marker. At 2504, method 2500 may include administering general anesthesia to the patient. At 2506, method 2500 may include placing the patient in a supine position with the patient's head turned to the side so that the labeled ear faces upward. At step 2508, method 2500 may include preparing the ear with an antiseptic (e.g., povidone-iodine, iodopovidone, betadine, vocadine, pyodine, and/or other suitable antiseptics) and draping the ear and surrounding area (e.g., covering the immediate area around the ear and/or otherwise creating sterile barrier around the ear while maintaining access to the ear to minimize the risk of infection and/or contamination). At 2510, method 2500 may include administering lidocaine, epinephrine and/or other anesthetics and epinephrine in a four-quadrant block to the ear canal. An operating microscope, endoscope, and/or distal tip camera 1004 may be used to accurately apply lidocaine and epinephrine. Among other things, the use of lidocaine and epinephrine may include a formulation containing about 1% lidocaine and epinephrine at a dilution of one part in eight thousand (1:8000). In some embodiments, endoscopic surgeons may use higher or lower concentrations of lidocaine or epinephrine depending on the volume of the formulation and the desired total dose of lidocaine or epinephrine per injection. In some embodiments, the volume of the composition is less than 1 ml per injection.

As shown in FIG. 25, steps 2512, 2514, and 2516 describe the system preparation steps 2400. The system preparation steps (2512, 2514, and 2516) may occur simultaneously, before and/or after the patient preparation steps (i.e., steps 2502, 2504, 2506, 2508, and 2510). . At step 2512, method 2500 may include sterilizing the device 10, for example, using a sterilization field (or, for example, using gamma irradiation or steam sterilization prior to packaging the device). At step 2514, method 2500 may include connecting tubing 36 to the proximal end 16 of device 10. At step 2516, method 2500 may include priming and purging system 2400 to ensure that air bubbles are removed from all lines and fluid is drawn into the pump. The 2400 system can be primed and cleaned using therapeutic fluid as a cleaning fluid. In one embodiment, a first amount of therapeutic fluid (e.g., about 8 μL to about 24 μL, or about 12 μL to about 20 μL, or about 16 μL) is pushed through the device 10 until droplets appear at the distal end 20 of the device. A second amount of therapeutic fluid (eg, about 3 μL to about 7 μL, or about 5 μL) is then pushed through the device 10 to ensure sufficient cleaning of the device. At step 2518, when the system and patient are prepared, method 2500 may include working with a posterior tympanomeatal flap so that device 10 can reach the oval and round windows in the middle ear. At step 2520, method 2500 may include removing a limited amount of bone at the junction of the bone canal and the eardrum using a microcurette or drill. At step 2522, method 2500 may include forming a hole in the base

- 19 046366 stapes (or fenestration of the base of the stapes), which is located on the opposite side of the cochlea as a round window, which allows for proper ventilation while delivering the solution to the inner ear. The hole at the base of the stapes can be created using an otological laser (eg KTP or CO2 otological laser). At step 2524, method 2500 may include removing overhanging bone (eg, pseudomembrane or overhanging bone protrusion) to expose the round window. Overhanging bone can be removed using a 1mm diameter diamond drill. At step 2526, method 2500 may include activating a distal tip camera 1004 (which may be incorporated into device 10) to assist with insertion and movement of device 10 into and along the external auditory canal.

As shown in FIG. 25, at step 2528, method 2500 may include introducing device 10 into the external auditory canal. At step 2528, method 2500 may include piercing a circular window with the distal end 20 of device 10 (step 2530) and passing through the circular window to a depth of no more than 1 mm (for example, an insertion depth of about 0.7 mm to about 1 mm, or about 0.8 mm to about 0.95 mm, or from about 0.85 mm to about 1.0 mm, or from about 0.85 mm to about 0.95 mm). The stop 28 may be positioned concentrically around the curved portion 32 of the needle 38 (or microneedle) at an appropriate location to ensure the proper depth of insertion of the needle 38 into the circular window. In some embodiments, the distal tip camera 1004 (or endoscope and/or surgical microscope) may be used (e.g., in conjunction with a monitor 2402 or display screen to which it is communicatively coupled) by the surgeon to ensure the proper depth of insertion of the device (step 2532). . Thus, the stop 28 may be used primarily to ensure that the 1.0 mm insertion depth is not exceeded, and the distal tip camera 1004 may be used to accurately position the device 10 prior to (and during) insertion of the needle 38 (or microneedle) into the round window. In other embodiments, the insertion depth may be greater than 1.0 mm and may include, for example, a depth of about 1.1 mm, about 1.2 mm, about 1.3 mm, about 1.4 mm, about 1.5 mm, about 1.6 mm, about 1.7 mm, and other spaces in between. At steps 2528, 2530 and/or 2532, method 2500 may include adjusting the angle or orientation of device 10 on the fly as needed during the procedure. Thus, although the angle of the tip 34 of the device 10 is fixed relative to the handle portion 12, the orientation of the tip 34 relative to the circular window membrane can be adjusted on the fly based on the angle or range of angles to which the surgeon orients the device 10. At step 2534, the method 2500 can enable the therapeutic fluid to flow through the device 10 at a selected flow rate for a selected duration of time.

As shown in FIG. 25, in some embodiments, the flow rate (or infusion rate) may include a rate of about 30 μL/min, or from about 25 μL/min to about 35 μL/min, or from about 20 μL/min to about 40 μL/min , or from about 20 μl/min to about 70 μl/min, or from about 20 μl/min to about 90 μl/min, or from about 20 μl/min to about 100 μl/min. In some embodiments, the selected length of time (i.e., the time during which the therapeutic fluid passes) may be about 3 minutes, or from about 2.5 minutes to about 3.5 minutes, or from about 2 minutes to about 4 minutes, or from about 1.5 minutes to about 4.5 minutes, or from about 1 minute to about 5 minutes. In some embodiments, the total volume of therapeutic fluid delivered to the inner ear may be about 0.09 ml, or from about 0.08 ml to about 0.10 ml, or from about 0.07 ml to about 0.11 ml. In some embodiments, the duration of the procedure may be less than a minute (eg, about 25 seconds to about 59 seconds, or about 30 seconds to about 55 seconds, or about 31 seconds to about 45 seconds). In some embodiments, the total volume of therapeutic fluid is from about 40% to about 50% of the volume of the inner ear. At step 2536, method 2500 may include monitoring the distribution of therapeutic fluid (or drug) in the inner ear, including the base, middle, and apex of the cochlea (e.g., through the distal tip camera 1004, an endoscope, and/or an operating microscope) to determine whether whether to adjust the depth of insertion of the device 10 into the round window (for example, deeper or shallower). For example, in one or more embodiments, cumulative volume may be monitored, and in other embodiments, fluorescent agents may be added to the therapeutic fluid, which may then be excited and/or activated through the optical fiber or distal tip chamber 1004 to allow visualization of distribution therapeutic fluid in the inner ear. At step 2538, method 2500 may include removing the device 10. At step 2540, method 2500 may include applying a skin treatment agent (e.g., Healon (sodium hyaluronate) or hyaluronic acid) to both the round window membrane and the stapes base, or any of these, to provide a functional seal to both areas (or either of these areas) while healing occurs over a subsequent period, for example, about 24 hours to about 48 hours. At 2542, method 2500 may include returning the posterior tympanomeatal flap to its original (biological) position. In some embodiments of the present invention, method 2500 may include performing one or more steps in an order different from that presented in FIG. 25, as well as additional steps not shown in FIG. 25. In some embodiments, one or more

- 20 046366 More steps may be skipped and/or performed simultaneously with at least one other step.

Some definitions

To make this disclosure clearer, certain terms are defined below. Additional definitions of the following terms and other terms are provided throughout this specification.

The apparatus, composition, or method described herein as containing or including one or more named elements or steps is non-limiting, meaning that said elements or steps are essential, but other elements may be added within the scope of the composition or method. or stages. To avoid verbosity, it should also be understood that any device, composition or method described as containing or including (or which includes) one or more specified elements or steps also describes a corresponding, more limited composition or method consisting essentially of (or which consists essentially of) the same named elements or steps, which means that the composition or method contains or includes the named essential elements or steps and may also contain or include additional elements or steps that do not significantly affect the main and new characteristic(s). i) composition or method. It is also intended that any device, composition or method described herein as containing or including one or more named elements or steps or consisting essentially of one or more named elements or steps also describes a corresponding, more limited and closed composition or method consisting of (or which consists of) specified elements or steps, excluding any other unspecified element or step. In any composition or method disclosed herein, known or disclosed equivalents of any named essential element or step may be substituted for that element or step.

As used herein, the singular form when referring to a feature of a formula means one or more or at least one.

As used herein, the term biocompatible refers to materials that do not cause significant harm to living tissue when in contact with such tissue, for example, in vivo. In some embodiments, the materials are biocompatible if they are suitable for insertion into the inner ear. In some embodiments, the materials are biocompatible as long as they are not toxic to cells. In some embodiments, materials are biocompatible if their addition to cells in vitro results in less than or equal to 20% cell death and/or their in vivo administration does not cause significant inflammation or other similar adverse effects. In some embodiments, the materials used for the described devices and systems are biocompatible and tested to meet Class II biocompatibility requirements (eg, devices with short residence times (less than 24 hours) and indirect circulation routes).

As used herein, the term disease, disorder and/or condition refers to any disease, disorder and/or condition that can be treated by accessing the inner ear. In some embodiments, the disease, disorder and/or condition is a hearing disorder (eg, hearing loss). In some embodiments, the disease, disorder and/or condition is an imbalance disorder. In some embodiments, the disease, disorder and/or condition is a tumor, such as a tumor of the inner ear. In some embodiments, the disease, disorder and/or condition is a tumor, such as a vestibular schwannoma. Other diseases, disorders and/or conditions include, but are not limited to, acoustic neuroma, age-related vertigo and imbalance, autoimmune inner ear disease, benign paroxysmal positional vertigo, bilateral vestibular hypofunction, cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) and cholesteatoma.

As used herein, the term therapeutic fluid refers to a liquid formulation containing a drug or drug delivery mechanism to the inner ear, for example, a nucleic acid vector encoding the drug. A drug can be any agent, such as a small molecule or biological substance, whose function is to treat diseases or disorders, for example, hearing diseases, disorders and/or conditions, tumors, etc. In some embodiments, the drug is a viral gene preparation. In some embodiments, the drug is a therapeutic antibody. In some embodiments, the drug is a therapeutic antisense oligonucleotide. In some embodiments, the drug is a therapeutic nucleic acid (eg, RNA or DNA). In some embodiments, the drug is a therapeutic microRNA. In some embodiments, the drug is a therapeutic shRNA. In some embodiments

-

Claims (24)

the drug is a therapeutic CRISPR/Cas system containing a Cas protein and a guiding molecule, such as a guide RNA. In some embodiments, the drug is delivered to the inner ear as part of a therapeutic fluid. In some embodiments, the drug is encoded by a delivery method, such as a nucleic acid vector, that is delivered to the inner ear as part of a therapeutic fluid. In some embodiments, the drug is formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in a unit dose amount suitable for administration in a therapeutic regimen that shows a statistically significant likelihood of achieving a given therapeutic effect when administered to the appropriate target population. In some embodiments, the therapeutic fluid may be specifically configured to be administered by injection, that is, for example, an aqueous or non-aqueous solution or suspension. As used herein, the term pharmaceutically acceptable, which for example may be used in relation to a carrier medium used to prepare a therapeutic liquid as disclosed herein, means that the carrier medium is compatible with and is not harmful to the other ingredients of the liquid formulation. recipient. As used herein, the term treat (also treatment) refers to any administration of a drug (also therapy) that partially or completely alleviates, mitigates, eliminates, reverses, relieves, suppresses, delays the onset of, reduces the severity of, and/or reduces the incidence of one or more more symptoms, signs and/or causes of a particular disease, disorder and/or condition. In some embodiments, such treatment may be administered to a patient who has no signs of the corresponding disease, disorder and/or condition, and/or to a patient who has only early signs of the disease, disorder and/or condition. Alternatively or additionally, such treatment may be administered to a patient with one or more established symptoms of the relevant disease, disorder and/or condition. In some embodiments, treatment may be administered to a patient who has been diagnosed with a corresponding disease, disorder and/or condition. In some embodiments, treatment may be administered to a patient known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing a given disease, disorder and/or condition. In some embodiments, the patient may be a human. As used herein, the term essentially refers to the qualitative state of exhibiting a full or nearly full degree or extent of a characteristic or property of interest. Equivalents It should be understood that although the invention has been described in conjunction with the detailed description thereof, the foregoing description is intended to be illustrative and does not limit the scope of the claims. Other aspects, advantages and modifications are within the scope of the claims. This written description uses examples to disclose the invention, including the best embodiment, and to enable any person skilled in the art to practice the recited embodiments, including the manufacture and use of devices or systems and the performance of the recited methods. The patentable scope of embodiments of the present invention is defined by the claims and may include other examples that will be apparent to those skilled in the art. Such other examples are intended to be within the scope of the claims if they include structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with immaterial differences from the literal language of the claims. CLAIM 1. A device for delivering fluid to the ear, containing: a handle portion comprising a proximal end and a distal end; a telescopic support connected to the distal end of the handle portion and containing a plurality of hypotubes inserted into each other; a needle subassembly connected to the distal end of the telescopic support, the needle subassembly comprising a curved needle that includes: an angled tip for piercing at least one membrane; and a curved part; and a tube connected to the proximal end of the handle portion, wherein a curved needle extends through the hollow interior of the handle portion and is in fluid communication directly with the tube, wherein the curved needle is located concentrically in the innermost inserted hypotube of the plurality of hypotubes. - 22 046366 2. The device according to claim 1, characterized in that the telescopic support contains a plurality of hypotubes inserted into each other, each of which has a caliber from 10 to 30 and contains stainless steel. 3. A device according to any of the previous paragraphs, containing: a strain relief member coupled to the proximal end of the handle portion, wherein the strain relief member prevents kinking and/or deformation of the tube, and wherein the strain relief member comprises laminated projections. 4. A device as claimed in any one of the preceding claims, comprising a distal tip chamber located within a needle subassembly. 5. A device according to any of the previous claims, characterized in that the curved part of the curved needle has a length of from 0.5 to 5 mm, and the angle of the angled tip is from 20 to 70°, and wherein the angled tip protrudes from the curved part a curved needle to form an outlet for dispensing liquid. 6. A device as claimed in any one of the preceding claims, comprising a stopper coupled to a curved needle and shaped and sized to fit into the inner ear and control the distance the angled tip protrudes into the cochlea. 7. The device according to any of the previous claims, characterized in that the stopper has the shape of a cylindrical disk with a diameter from 0.2 to 1.2 mm and a height from 0.2 to 1.0 mm, and the stopper is molded in place on a curved needle on at a distance of 0.2 to 1.2 mm from the distal end of the angled tip, wherein the stop prevents insertion of the curved needle into the at least one membrane beyond a desired amount, and wherein the stop is mounted around a groove for securing the stop located within the curved needle. 8. A device according to any of the previous paragraphs, characterized in that the handle part additionally contains: machined grooves for tactile sensitivity and control; and a conical portion located at a distal end of the handle portion, and the telescopic support is connected to the distal end of the conical portion, the conical portion having a larger diameter at the proximal end than the distal end, and the telescopic support including a larger diameter at the proximal end than the distal end. . 9. A device as claimed in any one of the preceding claims, wherein the tubing is connected to the curved needle by a compression fit, the tubing comprising polyetheretherketone (PEEK), the tubing having an internal diameter of 0.003 to 0.01 inches, and the tubing having an outer diameter of 1 /64 to 1/16 inch, and the tube is more than 20 inches long. 10. The device according to claim 3, additionally containing: at least one machined boss located at a proximal end of the handle portion, the at least one machined boss interacting with the strain relief member and preventing axial movement between the handle portion and the strain relief member; and a ring reinforcement located at the interface between the telescopic support and the handle part. 11. A system for delivering a therapeutic fluid to a portion of the patient's inner ear, comprising: device according to any of the previous paragraphs; a sterilized syringe in fluid connection to a tube; and a pump in fluid communication with the tubing, the pump controlling the flow rate of liquid through the device at a level of from 10 μL/min to 200 μL/min. 12. A system for delivering a therapeutic fluid to a portion of the patient's inner ear, comprising: means for working with the posterior tympanomeatal flap; means for creating an opening at the base of the stapes of the inner ear; and a fluid delivery device comprising a needle located at a distal end of the fluid delivery device, the needle being configured to pierce a round window of the inner ear, the fluid delivery device comprising: a telescopic support containing a plurality of hypotubes inserted into each other; and a needle subassembly coupled to the distal end of the telescopic support, the needle subassembly comprising a curved needle disposed concentrically in the innermost inserted hypotube of the plurality of hypotubes; wherein the liquid delivery device is configured to be positioned at the desired - 23 046366 insertion depth in a round window; wherein the fluid delivery device is configured to deliver the therapeutic fluid to the inner ear, and wherein the therapeutic fluid comprises at least one viral gene preparation. 13. The system according to claim 12, additionally including: image forming device; and a monitor communicatively coupled to the imaging device, the monitor being visible to the surgeon; wherein the imaging device is activated before the circular window is pierced; wherein the imaging device is configured to monitor at least one of a flow rate of the therapeutic fluid and a distribution of the therapeutic fluid throughout the inner ear, wherein the imaging device comprises at least one of a distal tip camera, an endoscope, and an operating microscope. 14. The system according to claim 12, characterized in that the means for working with the posterior tympanomeatal flap comprises at least one of a micro-curette and a drill for cutting the posterior tympanomeatal flap. 15. The system according to claim 12, additionally containing: means for preparing and draping the ear prior to working with the posterior tympanomeatal flap, the patient being positioned prior to preparing and draping the ear; means for applying anesthesia before positioning the patient; and a means to mark the ear prior to the application of anesthesia. 16. The system according to claim 12, additionally containing: upstream pump; a tube for connecting between the fluid delivery device and an upstream pump; wherein the tube is connected before working with the posterior tympanomeatal flap; and means for sterilizing the fluid delivery device prior to handling the posterior tympanomeatal flap; Moreover, the system is primed before working with the posterior tympanomeatal flap. 17. The system according to claim 12, characterized in that: the system comprises at least one skin treatment agent configured to be applied to at least one of the round window membrane and the stapes base after removal of the fluid delivery device; and the system further comprises means for returning the posterior tympanomeatal flap to its original position after application of at least one skin treatment agent, wherein the at least one skin treatment agent comprises at least one of sodium hyaluronate and hyaluronic acid. 18. The system according to claim 12, further comprising means for removing bone from the junction of the bony canal and the tympanic membrane and/or the overhanging bone of the pseudomembrane after working with the posterior tympanomeatal flap, wherein the means for removing bone comprises at least one of a diamond drill and an otological drill. 19. The system according to claim 12, characterized in that the means for creating an opening in the base of the stapes contains an otological laser. 20. The system of claim 12, further comprising means for applying at least one of an anesthetic and epinephrine to the patient's ear canal prior to handling the posterior tympanomeatal flap. 21. The system of claim 15, wherein the ear preparation comprises a means for applying at least one antiseptic to the ear, wherein the at least one antiseptic contains at least one of povidone-iodine, iodopovidone, betadine, vocadine and piodina. 22. The system of claim 12, wherein the desired insertion depth includes a depth of 0.7 to 1.0 mm. 23. The system according to claim 12, characterized in that the fluid delivery device is configured to deliver therapeutic fluid to the inner ear at a flow rate from 20 μl/min to 100 μl/min, and the fluid delivery device is configured to deliver complete volume of therapeutic fluid in the range from 0.07 to 0.11 ml, and wherein the fluid delivery device is configured to deliver the therapeutic fluid over a period of time in the range from 0.5 to 5 minutes. 24. A system for delivering a therapeutic fluid to a portion of the patient's inner ear, comprising: means for performing transcanal tympanotomy; means for preparing the patient's round window; means for performing laser microstapedotomy; -