Hand tool to assist insertion of transround window membrane catheters for short-term and long-term delivery of drugs to the inner ear via a micropump

Abstract

The present solution provides a system and method for transround window membrane drug delivery. In summary, the system includes a micropump connected to a flexible cannula. The cannula can be threaded through a handpiece that can be used to pierce a patient's round window membrane. The handpiece allows the cannula to be inserted into the round window membrane, improving distribution of the delivered drug throughout the inner ear. The present solution can function as a small, implantable or wearable device that can be used for chronic and acute transround window membrane drug delivery. This configuration allows the micropump to deliver small amounts of drug from an internal reservoir continuously or intermittently over a period of days to months.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 938,561, entitled "HAND TOOL FOR AIDING IN INSERTION OF A TRANS-ROUND WINDOW MEMBRANE CATHETER FOR MICROPUMP-MEDIATED ACUTE AND CHRONIC INNER-EAR DRUG DELIVERY," filed November 21, 2019, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Advances in pharmacological technology have resulted in several compounds for treating sudden noise and age-related hearing loss. While these new compounds have shown promising results, many are ineffective when delivered systemically due to the blood-cochlear barrier, and local delivery via attachment to the patient's round window membrane is often ineffective because the compound may have low permeability through the round window membrane. Low compound permeability can result in concentration levels of the delivered compound below the therapeutic threshold. Summary of the Invention [Problem to be solved by the invention]

[0003] This disclosure describes systems and methods that can provide a robust medical practice for the effective localized delivery of pharmaceuticals (or, more generally, compounds) to the inner ear. The systems and methods can deliver compounds to the inner ear via a trans-round window membrane approach using a cannula (also referred to herein as a catheter) inserted through the round window membrane and connected to an implantable micropump. The micropump can deliver compounds short-term or long-term. The micropump can control the amount of compound delivered directly into the perilymphatic fluid in the scala tympani. The systems and methods overcome many of the challenges associated with intratympanic injection, such as low drug penetration through the round window membrane, uneven drug distribution throughout the inner ear, and poor drug bioavailability within the cochlea. The systems and methods can be applied to both pharmacokinetic studies in in vivo drug discovery and the treatment of inner ear diseases in humans. Transround window membrane drug delivery is compatible with many drug classes, including small molecules and large, complex molecules such as proteins, viruses, and liposomes.

[0004] The systems and methods of the present disclosure can also be used to overcome the difficulties associated with implanting a cannula in a patient for long-term treatment. For example, the present disclosure provides a tool, referred to herein as a handpiece, that can be used to facilitate the insertion of a cannula through the round window membrane or other anatomical membrane in a patient's ear. The cannula can be threaded through a channel provided in the handpiece and used to pierce the round window membrane. The handpiece can then be withdrawn from the middle ear, but the cannula remains behind due to friction between the cannula and the round window membrane. The cannula can also be provided with a bleb or stopper to facilitate anchoring the cannula within the round window membrane and controlling the depth to which the cannula protrudes into the inner ear. [Means for solving the problem]

[0005] At least one aspect of the present disclosure is directed to a method for delivering fluid to the inner ear. The method can include introducing a cannula into a channel defined by a tool shaft of a handpiece. The handpiece can include a tip portion coupled to the tool shaft and including an outlet in communication with the channel. The handpiece can include a collar coupled to the tip portion a predetermined distance from the outlet. The collar can be configured to engage an anatomical structure of the patient and control the distance the tip portion protrudes into the patient's cochlea. The method can include piercing an anatomical membrane covering the anatomical structure of the patient with the tip portion of the handpiece. The method can include implanting the cannula into the patient through the outlet of the handpiece. The cannula can include a first end coupled to a micropump and a second end including a stopper. The stopper can be configured to allow insertion of the tip of the cannula through the anatomical membrane into the patient's cochlea. The method can include placing the stopper of the cannula in the anatomical structure of the patient. The method may include removing the handpiece from the patient's ear.

[0006] In some implementations, the method can include implanting a micropump in a patient. The micropump can include a drug reservoir storing a compound. In some implementations, the method can include pumping the compound from the drug reservoir through the cannula to the patient's cochlea with the micropump. In some implementations, the method can include withdrawing a predetermined volume of fluid from the patient's cochlea with the micropump in response to pumping the compound from the drug reservoir through the cannula to the cochlea. In some implementations, the micropump can include a first valve, a second valve, a pump, a loading chamber, and an outlet in fluid communication with the cannula.

[0007] In some implementations, the method may include drawing the compound from the drug reservoir into the loading chamber by opening a first valve and activating a pump. In some implementations, the method may include forcing the compound through an outlet of the cannula by closing the first valve, opening a second valve, and activating a pump. In some implementations, the method may include securing the cannula in place using at least one of a stopper or glue before removing the handpiece from the patient's ear. In some implementations, the method may include supplying an additional volume of the compound to the drug reservoir via an external reservoir. In some implementations, the method may include selecting a length of the tip portion of the handpiece in response to a computed tomography scan or a magnetic resonance imaging scan of the patient.

[0008] At least one other aspect of the present disclosure is directed to a system. The system can include a cannula. The cannula can have a first end coupled to a micropump. The cannula can have a second end including a stopper. The stopper can be configured to allow insertion of a tip of the cannula through an anatomical membrane into the patient's cochlea. The system can include a handpiece configured to introduce the cannula into the patient. The handpiece can include a channel defined by a tool shaft of the handpiece. The channel can be configured to receive the cannula. The handpiece can include a tip portion coupled to the tool shaft and including an outlet in communication with the channel. The tip portion can be configured to pierce the patient's anatomical membrane. The handpiece can include a collar coupled to the tip portion a predetermined distance from the outlet. The collar can be configured to seat against the patient's anatomical structure and control the distance the tip portion can protrude into the patient's cochlea. The handpiece may be configured to be withdrawn from the patient's ear in response to placing the cannula within the patient's anatomy.

[0009] In some implementations, the micropump can be implanted in a patient. In some implementations, the micropump can include a drug reservoir storing a compound. In some implementations, the micropump can pump the compound from the drug reservoir through the cannula to the patient's cochlea. In some implementations, the micropump can extract a predetermined volume of fluid from the patient's cochlea after pumping the compound from the drug reservoir through the cannula to the cochlea. In some implementations, the micropump can include a first valve, a second valve, a pump, a loading chamber, and an outlet in fluid communication with the cannula. In some implementations, the micropump can extract the compound from the drug reservoir into the loading chamber by opening the first valve and activating the pump. In some implementations, the micropump can push the compound through the outlet of the cannula by closing the first valve, opening the second valve, and activating the pump.

[0010] In some implementations, the handpiece can include an angled portion connecting the tip portion to the tool shaft. The angled portion can have a channel and a second channel in communication with the outlet of the tip portion. In some implementations, at least one of the angled portion or the tip portion can be separable from the tool shaft and can be joined together using one or more of a snap connector, a friction fit connection, a press fit connection, a knurled nut, or a luer lock connection. In some implementations, the angled portion, the tip portion, and the tool shaft are fabricated from a single, continuous piece of material including at least one of stainless steel or plastic. In some implementations, at least one of the angled portion or the tip portion can rotate about an axis parallel to the length of the tool shaft while remaining connected to the tool shaft.

[0011] In some implementations, the tip section of the handpiece comprises a needle tip. In some implementations, the needle tip is capable of piercing an anatomical membrane of a patient. In some implementations, the outlet of the tip section is located at the distal end of the tip section. In some implementations, the distal end of the tip section forms an angle between the outlet and the tip section, the angle being between 70° and 170°, between 75° and 130°, between 90° and 120°, or between 110° and 120°. In some implementations, the length of the tool shaft is between about 130 mm and about 170 mm, between about 140 mm and about 160 mm, or between about 140 mm and about 150 mm.

[0012] These and other aspects and implementations are discussed in detail below. The above information and the following detailed description, including examples illustrating various aspects and implementations, provide an overview or framework for understanding the nature and characteristics of the claimed aspects and implementations. The drawings, which illustrate and provide a further understanding of the various aspects and implementations, are incorporated into and constitute a part of this specification. It will be readily understood that aspects can be combined with one another, and that features described in the context of one aspect of the invention can be combined with other aspects. The aspects can be implemented in any convenient form.

[0013] The accompanying drawings are not intended to be drawn to scale. Like reference numbers and designations in the various drawings indicate like elements. For purposes of clarity, not every component may be labeled with a reference number in every drawing. The above and other objects, aspects, features, and advantages of the present disclosure will become more apparent and will be better understood by reference to the following description taken in conjunction with the accompanying drawings. [Brief explanation of the drawings]

[0014] [Figure 1] 1 is an exemplary handpiece for delivering fluid to a patient's inner ear, according to one or more implementations. [Figure 2]FIG. 2 is a side view of the exemplary handpiece shown in FIG. 1 according to one or more implementations. [Figure 3] FIG. 2 is a cross-sectional view of the exemplary handpiece shown in FIG. 1 according to one or more implementations. [Figure 4] FIG. 2 is a side view of the exemplary handpiece shown in FIG. 1 according to one or more implementations. [Figure 5] 2 is an exemplary tip portion of the handpiece shown in FIG. 1 according to one or more implementations. [Figure 6] 1 is an exemplary handpiece having a compression fitting, according to one or more implementations. [Figure 7] FIG. 2 is an enlarged view of the tip of the exemplary handpiece shown in FIG. 1, according to one or more implementations. [Figure 8A] 1 illustrates an exemplary handpiece tip inserted into the round window, according to one or more implementations. [Figure 8B] 1 illustrates an exemplary handpiece tip inserted into the round window, according to one or more implementations. [Figure 9] 1 is an exemplary system for injecting a compound into the inner ear, according to one or more implementations. [Figure 10] FIG. 10 is a top view of an exemplary micropump for use in the exemplary system shown in FIG. 9, according to one or more implementations. [Figure 11] 10 is an exemplary tip of a cannula that can be used in the exemplary system shown in FIG. 9, according to one or more implementations. [Figure 12] The exemplary handpiece of FIG. 1 according to one or more implementations is illustrated together with the exemplary cannula of FIG. 9 in a configuration that can be used to facilitate placement of the cannula within a patient's round window membrane. [Figure 13] FIG. 10 is a block diagram of an exemplary method for flushing fluid into a patient's inner ear using the exemplary system shown in FIG. 9, according to one or more implementations. [Figure 14]Pharmacokinetic (PK) plots of different delivery methods, according to one or more implementations. [Figure 15] 1 is a plot of the pharmacodynamics (PD) of different delivery methods, according to one or more implementations. DETAILED DESCRIPTION OF THE INVENTION

[0015] The various concepts introduced above and further detailed below can be implemented in any of numerous ways, as the described concepts are not limited to any particular implementation manner, and examples of specific implementations and applications are provided primarily for illustrative purposes.

[0016] The solution provides transround window membrane drug delivery. Generally, the system can include a micropump connected to a flexible cannula. The cannula can be inserted through the round window membrane using a handpiece-type tool. The solution can function as a small, implantable or wearable device that can be used for both long-term and short-term transround window membrane drug delivery. With this configuration, the micropump can deliver small amounts of drug continuously or intermittently from an internal reservoir over a period of days to months. In some implementations, a syringe pump can be used for short-term medical procedures. The micropump can drive a fluid flow through the cannula to deliver multiple doses on a preprogrammed schedule. The solution is suitable for timed sequential delivery of a series of several active substances.

[0017] The present solution can be used instead of (or in conjunction with) systemic drug delivery. Systemic delivery may require a higher dose of the compound compared to the local delivery of the compound achieved by the present solution. The higher doses associated with systemic delivery often result in undesirable side effects that, in some cases, may deter the patient from continuing treatment. Furthermore, once systemically administered drugs pass through the hepatic system, they are often modified by enzymes in the liver cells, further reducing drug activity and resulting in ineffective therapeutic effects in the inner ear. By delivering the compound directly to the inner ear, the present solution overcomes these challenges associated with systemic drug delivery because the compound is infused directly into the cochlear fluid. Injecting the compound directly into the cochlear fluid allows for a smaller dose compared to systemic delivery.

[0018] The present disclosure also provides a tool, referred to herein as a handpiece, that can be used to facilitate the insertion of a cannula through a patient's anatomical membrane, such as the round window membrane. The handpiece can be operated, for example, by a surgeon. A cannula can be threaded through a channel provided in the handpiece and used to pierce the round window membrane. The handpiece can then be withdrawn from the middle ear, with the cannula remaining behind due to friction between the cannula and the round window membrane. The cannula can also be provided with a bleb or stopper to facilitate anchoring the cannula within the round window membrane and controlling the depth to which the cannula protrudes into the inner ear. The handpiece and cannula, as well as techniques for using both, are further described below.

[0019] FIG. 1 illustrates an exemplary handpiece 100 for delivering fluid to a patient's inner ear. The fluid may be any therapeutic substance or agent. The handpiece 100 includes a tool shaft 102, an angled portion 104, and a tip portion 106. The tip portion 106 may further include a collar 108. The handpiece 100 is inserted into a patient's ear canal 110 for transmural delivery of fluid to a cochlea 112 via a round window 114. The tip portion 106 can be used to pierce the round window membrane, allowing fluid to be delivered to the cochlea 112.

[0020] The tool shaft 102 can be held in a surgeon's hand or a robotic surgical device and can define a cavity or channel through its center. The channel can be similar to the microfluidic channel 300, described later in this specification in conjunction with FIG. 3, for example. The tool shaft 102 can be fabricated from a variety of materials, including metals such as aluminum, stainless steel, or other alloys or metals. In some implementations, the tool shaft 102 can be fabricated from one or more plastics or polymers, such as ethylene chlorotrifluoroethylene (ETCFE), ethylene tetrafluoroethylene (ETFE), fluorinated ethylene propylene (FEP), polychlorotrifluoroethylene (PCTFE), polyetheretherketone (PEEK), perfluoroalkoxyalkane (PFA), polyphenylene sulfide (PPS), polyphenylsulfone (PPSU), or polysulfone (PSU), among others. The tool shaft 102 can be fabricated as a thin shaft, with a length greater than its overall width, to facilitate positioning of the tip portion 106 within the patient's ear. However, it should be understood that other configurations of the tool shaft 102 are possible to facilitate positioning of the handpiece within the desired anatomy of the patient.

[0021] The angled portion 104 may be angled to facilitate positioning the tip portion 106 within a patient's anatomical structure, such as the round window membrane. The angled portion 104 may be manufactured as a separate component of the handpiece 100, allowing the angled portion 104 to be attached to or detached from the tool shaft 102 as needed. If manufactured as a separate tool, the angled portion 104 may be coupled to the tool shaft 102 using some type of connector, such as a gasket, O-ring, snap connector, friction fit connection, press fit connection, or Luer lock connection, among others. The angled portion 104 may include a second microfluidic channel in communication with the microfluidic channel of the tool shaft 102, allowing fluid or a cannula to be transported through the channel of the tool shaft 102, the angled portion 104, the tip portion 106, and to an outlet of the tip portion 106. In some implementations, the tool shaft 102 and angled portion 104 may be manufactured as a single, continuous piece of one material or combination of materials, as described herein.

[0022] The angle of the angled portion 104 can be selected depending on the anatomical characteristics of a patient undergoing a medical procedure using the handpiece 100. For example, different angles of the angled portion 104 can facilitate positioning of the tip portion 106 within the ear canal 110. The angled portion can be manufactured from a variety of materials, such as aluminum, stainless steel, or other alloys or metals. In some implementations, the angled portion 104 can be manufactured from one or more plastics or polymers, such as ethylene chlorotrifluoroethylene (ETCFE), ethylene tetrafluoroethylene (ETFE), fluorinated ethylene propylene (FEP), polychlorotrifluoroethylene (PCTFE), polyetheretherketone (PEEK), perfluoroalkoxyalkane (PFA), polyphenylene sulfide (PPS), polyphenylsulfone (PPSU), or polysulfone (PSU), among others. The angled portion 104 can be manufactured to have a degree of flexibility to better allow the tip portion to pass through the patient's ear canal 110 or the patient's middle ear. In some implementations, the angled portion 104 is not present, and instead the handpiece 100 comprises a tool shaft 102 and a tip portion 106 .

[0023] The tip portion 106 can be manufactured as part of the tool shaft 102 or as part of the angled portion 104. In some implementations, the tip portion 106 can be detachable from either the tool shaft 102 or the angled portion 104. In some implementations, any combination of handpiece portions can be manufactured as a single piece. For example, the tip portion 106 and the angled portion 104 can be manufactured as a single piece of one or more materials, the tool shaft 102 and the angled portion 104 can be manufactured as a single piece of one or more materials, or the tool shaft 102 and the tip portion 106 can be manufactured as a single piece of one or more materials (e.g., in implementations where the angled portion 104 is not present). The tip portion 106 can be manufactured from a variety of materials, such as aluminum, stainless steel, or other alloys or metals. In some implementations, the tip portion 106 may be manufactured from one or more plastics or polymers, such as ethylene chlorotrifluoroethylene (ETCFE), ethylene tetrafluoroethylene (ETFE), fluorinated ethylene propylene (FEP), polychlorotrifluoroethylene (PCTFE), polyether ether ketone (PEEK), perfluoroalkoxyalkane (PFA), polyphenylene sulfide (PPS), polyphenylsulfone (PPSU), or polysulfone (PSU), among others.

[0024] 1 , the tip portion 106 may be tapered along its length for easier positioning through a patient's ear canal 110 and into the middle ear for cannula or other fluid delivery purposes. The tip portion 106 may define a microfluidic channel in a central portion of the tip portion 106 so that fluid transferred through a microfluidic channel in the tool shaft 102 or angled portion 104 can be transferred through the tip portion 106 to an outlet in the tip portion 106. The tip portion may include a collar 108, which may be placed around a grooved region of the tip portion 106 or may be secured to the tip portion 106 using glue or another type of adhesive. In some implementations, the collar 108 is fabricated from the same piece of material as the tip portion 106.

[0025] The tip portion 106 can have a shape configured to rest against a patient's anatomical structure, such as the round window 114. The tip portion 106 can have outlets for microfluidic channels defined in the tool shaft 102, the angled portion 104, and the tip portion 106, and the tool shaft 102, the angled portion 104, and the tip portion 106 can each be in communication with one another. The outlets in the tip portion 106 can be located at a needle tip of the tip portion 106. The needle tip of the tip portion 106 can extend into the patient's cochlea 112.

[0026] FIG. 2 shows a side view of an exemplary handpiece 100. The handpiece 100 includes a tool shaft 102, an angled portion 104, and a tip portion 106. A surgeon can use the tool shaft 102 to hold and manipulate the handpiece 100 and the position of the tip portion 106. The outer surface of the tool shaft 102 can include knurling to allow the surgeon to improve their grip on the handpiece 100. In some implementations, one or more portions of the handpiece 100 can be coupled to a surgical robot. In such implementations, portions of the handpiece 100 can include fasteners or other coupling devices or structures that can couple the handpiece to a surgical robot. The tool shaft 102 can include a proximal end 200 and a distal end 202. The tool shaft 102 can have a diameter of approximately 4 mm, 5 mm, or 6 mm. The tool shaft 102 can have a length of approximately 90 mm to approximately 150 mm, approximately 90 mm to approximately 130 mm, or approximately 100 mm to approximately 120 mm. In some implementations, the length of the tool shaft 102 is 110 mm.

[0027] The distal end of the tool shaft 102 may be coupled to the proximal end 204 of the angled portion 104. The tip portion 106 is coupled to the distal end 206 of the angled portion 104. The angled portion 104 is angled so that the tip portion 106 can pass through an ear canal (e.g., ear canal 110 shown in FIG. 1 ) and reach the round window or another anatomical structure within a patient's ear during a minimally invasive medical procedure. The angled portion 104 forms an angle 208 between the tool shaft 102 and the tip portion 106. The angle 208 may be between about 170° and about 90°, between about 170° and about 110°, between about 170° and about 120°, between about 170° and about 140°, or between about 165° and about 155°. Angle 208 can be defined as the angle between the longitudinal axis of tool shaft 102 and the longitudinal axis of tip portion 106. Angle 208 is configured to allow trans-meatal positioning of tip portion 106 at the patient's round window. Angle 208 can be selected to allow the surgeon to position tip portion 106 at the round window and to allow the surgeon to visualize the ear canal.

[0028] The tip section 106 may be coupled to the distal end 206 of the angled section 104. The distal portion of the tip section 106 may be angled 210. The angle 210 may be between about 70° and about 140°, between about 75° and about 130°, between about 90° and about 120°, between about 100° and about 120°, or between about 110° and about 120°. For example, the angle 210 may be about 105°, 106°, 107°, 108°, 109°, 110°, 111°, 112°, 113°, 114°, 115°, 116°, 117°, 118°, 119°, or 120°. The angle 210 may be selected to position the distal portion of the tip section 106 substantially perpendicular to the round window when the handpiece 100 is inserted through the ear canal. The angle 210 can be selected depending on the anatomy of the patient's inner or middle ear. For example, a surgeon can select a handpiece 100 with an appropriate angle 210 depending on the location and angle of the round window and round window fossa. In some implementations, a surgeon can use CT or MRI images of the middle and inner ear to determine which angle 210 to select. The handpiece 100 can also be manufactured with different angle 210 configurations. In some implementations, a surgeon can bend the tip portion 106 to change the angle 210 during a medical procedure.

[0029] The tip portion 106 may include a collar 108. The collar 108 may be configured to rest within the round window. For example, the collar 108 may be fabricated from a semi-flexible material that can conform to the round window in the patient's middle ear or to different anatomical structures within the patient's ear. The collar 108 may be rigid enough to prevent more of the handpiece 100 from extending into the patient's cochlea (e.g., cochlea 112 shown in FIG. 1 ) than desired. The flexible conformability of the collar 108 may allow a seal to be formed with one or more anatomical structures in the patient's middle ear. For example, once the tip portion 106 pierces the round window membrane, the collar 108 may seal the round window. The collar 108 may also control the depth to which the end of the tip portion 106 can be inserted into the cochlea. The collar 108 may include medical-grade silicone or another type of semi-flexible or biocompatible material. The shape of collar 108 may be substantially dome-shaped or hemispherical, and the diameter of collar 108 at its widest point may be about 0.5 mm to about 3 mm, about 0.5 mm to about 2.5 mm, about 1 mm to about 2 mm, or about 1.5 mm to about 2 mm.

[0030] The handpiece 100 can have an overall length 212 of about 130 mm to about 170 mm, about 140 mm to about 160 mm, or about 140 mm to about 150 mm. While the tool shaft 102, angled portion 104, and tip portion 106 are described as separate pieces, each of these can also be manufactured as a single or multiple pieces. For example, the handpiece 100 can include one piece, two separate pieces, or three separate pieces. The handpiece 100 can be separable at the boundaries between any of the tool shaft 102, angled portion 104, and tip portion 106. In some implementations, the presence of an interface between the tool shaft 102, the angled portion 104, and the tip portion 106 does not imply that the tool shaft 102, the angled portion 104, and the tip portion 106 are separable, such as when one or more of the tool shaft 102, the angled portion 104, or the tip portion 106 are formed from a single, continuous piece of material, or when one or more of the tool shaft 102, the angled portion 104, or the tip portion 106 are permanently or semi-permanently joined together. For example, the tool shaft 102, the angled portion 104, and the tip portion 106 may be manufactured as a single piece. In other implementations, the angled portion 104 and the tool shaft 102 can form a first piece, and the tip portion 106 can form a second piece. In some implementations, the handpiece 100 is reusable. In other implementations, the handpiece 100 is disposable. Handpiece 100 may be made from a medically approved, sterilizable material. For example, handpiece 100 may be made from 316 stainless steel or any other type of metal described herein, or a sterilizable plastic or polymer described herein.

[0031] FIG. 3 shows a cross-sectional view of an exemplary handpiece 100. The handpiece 100 includes a microfluidic channel 300. The microfluidic channel 300 includes an inlet 302 and an outlet 304. The inlet 302 may be coupled to a reservoir, which is further described in connection with FIGS. 9 and 10. The microfluidic channel 300 may have an approximately 22 gauge. The gauge of the microfluidic channel may also be about 12 to 28, about 16 to 24, about 18 to 22, or about 20 to 22. The microfluidic channel 300 may have a dead volume of about 10 μL to about 25 μL, about 15 μL to about 25 μL, or about 20 μL to about 25 μL.

[0032] The microfluidic channel 300 can also comprise separate portions. For example, the tool shaft 102, the angled portion 104, and the tip portion 106 can each comprise separate portions of the microfluidic channel 300. These separate portions can be a single, uninterrupted channel. In some implementations, the microfluidic channel 300 can be separated at an interface between one or more of the separate portions. In some implementations, the microfluidic channel portions can be separated near an interface between separate portions of the hand piece 100. For example, the microfluidic channel portion in the tip portion 106 can extend beyond the tip portion 106 (as shown in FIG. 4 ), and the microfluidic channel portion in the angled portion 104 can terminate short of the distal end 206, such that the angled portion 104 can receive the portion of the microfluidic channel extending from the tip portion 106. In some implementations, the hand piece 100 can comprise multiple microfluidic channels 300. For example, the hand piece 100 can comprise different microfluidic channels 300 for delivering different therapeutic agents. In some implementations, the second microfluidic channel 300 can be used to remove fluid from the cochlea. The microfluidic channel 300 may be configured to accommodate or place a cannula, such as the cannula 904 described herein in conjunction with FIG. 9, within the patient's cochlea 112.

[0033] FIG. 4 shows a side view of an exemplary handpiece 100. In some implementations, one or more of the portions of the handpiece 100 are separable from one another. FIG. 4 shows an exemplary handpiece 100 with a separable tip portion 106. The tip portion 106 can be separated from the tool shaft 102 and the angled portion 104 to facilitate sterilization of the handpiece 100. The tip portion 106 can be separable from the angled portion 104 so that the tip portion 106 can be reconnected with the angled portion 104 at a different rotational angle. The tip portion 106 can be rotated relative to the angled portion 104 without separating the tip portion 106 from the angled portion 104. The tip portion 106 can be rotated relative to the angled portion 104 to improve a surgeon's access to the round window. For example, a surgeon or surgical robot can adapt the initial position of the tip portion 106 to account for variations in patient anatomy. The handpiece 100 can include gaskets or O-rings at the interfaces between the separable portions. The separable parts may be joined together by snap connectors, friction or press fit connections or luer lock connections.

[0034] FIG. 5 illustrates an exemplary tip section 106 for an exemplary hand piece 100. The tip section 106 illustrated in FIG. 5 is separated from the angled portion 104 and tool shaft 102 of the hand piece 100. The tip section 106 can include a tip 500. The tip 500 can be part of, or can include a portion of, the microfluidic channel 300 extending from the body of the tip section 106. In some implementations, the entire tip section 106 can be rotated relative to the angled portion 104. In other implementations, the tip 500 can be rotated within the tip section 106. In either example, the tip 500 can be rotated from the position illustrated in FIG. 4 to a second position 502, shown by the dotted line. As illustrated, the tip 500 can be bent or angled to facilitate placement of the collar 108 on an anatomical structure within a patient's middle ear, such as the round window. The bent portion of tip 500 can form an angle between the outlet of tip portion 106 and the body of tip portion 106, the angle being between about 90° and about 175°.

[0035] FIG. 6 shows an exemplary handpiece 100 having a compression fitting 600. The compression fitting 600 may be a knurled nut. The compression fitting 600 couples the angled portion 104 to the tip portion 106. Loosening the compression fitting 600 allows the tip portion 106 to be rotated relative to the angled portion 104. Once the surgeon selects the degree of rotation, they can tighten the compression fitting 600 to lock the degree of rotation between the angled portion 104 and the tip portion 106 in place. In other implementations, the tip portion 106 and the angled portion 104 can be held together by a friction fit that allows the tip portion 106 to rotate relative to the tip portion 106. In such implementations, the tip portion 106 and the angled portion 104 can be rotated the desired number of degrees of rotation and then pressed into the friction fit portion of the tool shaft 102 to lock the degree of rotation for the surgical procedure. The removable tip and angled section allow for the selection of tip materials and dimensions to suit the anatomy of the patient undergoing the medical procedure using handpiece 100.

[0036] FIG. 7 shows an enlarged view of the tip 500 of an exemplary handpiece 100. The tip 500 can include a needle tip 700. The needle tip 700 includes an outlet 304. The needle tip 700 can be blunt or beveled to form a pointed tip. The needle tip 700 can be configured to pierce the round window membrane or another anatomical structure in the patient's ear. The needle tip 700 can extend beyond the collar 108 by a length of about 1 mm to about 4 mm, about 2 mm to about 3 mm, or about 2.5 mm to about 3 mm. For example, the needle tip 700 can have a length of 2.7 mm. The needle tip 700 can have a gauge size of about 25 to about 30, about 26 to about 30, or about 27 to about 30. Once the collar 108 is seated within the round window, only the needle tip 700 protrudes into the cochlea. The collar 108 can control the depth to which the needle end 700 protrudes into the cochlea (such as the cochlea 112 shown in FIG. 1).

[0037] The needle end 700 can prevent the needle end 700 from protruding too far into the cochlea. The needle end 700 can prevent the needle end 700 from protruding too far into the cochlea and damaging the cochlea. The collar 108 can properly position the outlet 304 within the cochlea to properly distribute the therapeutic substance within the cochlea (e.g., cochlea 112 shown in FIG. 1 ). For example, if the outlet 304 is positioned too shallow within the cochlea, the therapeutic substance may concentrate near the round window and not distribute within the cochlea. If the outlet 304 is positioned too deep within the cochlea, the needle end 700 may cause damage or trauma to the cochlea. In some implementations, the tip 500 is fabricated from a malleable material so that a surgeon can bend the tip 500 to change the angle 210. The collar 108 may be coupled to the tip 500 with an adhesive. In some implementations, the tip 500 can include a groove in which the collar 108 rests.

[0038] 8A and 8B show the tip 500 inserted into the round window. FIG. 8A shows the handpiece 100 inserted through the ear canal with the tip 500 inserted into the round window 114 or another type of anatomical structure in the patient's ear. FIG. 8B shows a close-up of the tip 500 inserted into the round window 114 of FIG. 8A. The tip 500 can be used to pierce the round window membrane. The tip 500 can be inserted into the round window 114. The collar 108 can rest within the round window 114 and seal the round window 114 when fluid is infused into the cochlea 112. The collar 108 tapers from a diameter smaller than the diameter of the round window 114 to a diameter larger than the diameter of the round window 114. When the collar 108 is pressed against the round window 114, the collar 108 can occlude the round window 114. The collar 108 is also used to control the depth of insertion of the tip 500 into the cochlea 112. For example, the collar 108 can prevent the tip 500 from being inserted beyond the collar 108 into the cochlea. A portion of the collar 108 having a diameter larger than the diameter of the round window 114 can essentially stop the tip 500 from being inserted further into the cochlea 112. Moving the collar 108 toward the tip 500 exit 116 reduces the depth to which the tip 500 can be inserted. The collar 118 can prevent the tip 500 from being inserted too far into the cochlea 112.

[0039] 9 shows an exemplary system 900 for injecting a compound into the inner ear. The system 900 can include a micropump 902. The system 900 can include a cannula 904. The cannula 904 may also be referred to as a catheter 904. The cannula 904 may be coupled to an outlet 906 of the micropump 902. The cannula 904 can be inserted into the inner ear through a round window membrane 908. The cannula 904 can be inserted through the round window membrane 908 using the handpiece 100 described hereinabove.

[0040] The micropump 902 is further described, inter alia, in connection with FIG. 10 . Generally, the micropump 902 can be a reciprocating, automated fluid injection system. The micropump 902 can include an integrated drug reservoir. The drug stored in the drug reservoir may be referred to as a compound, and the drug reservoir may be referred to as a compound reservoir. The micropump 902 can eject the compound from the compound reservoir through the cannula 904 into the inner ear at predetermined intervals. The micropump 902 can be configured to both infuse the compound into the inner ear and withdraw fluid from the inner ear so that the net volume added to the inner ear is substantially zero. The micropump 902 can include one or more internal pumps and valves that can control the withdrawal and injection of fluid from and into the micropump. For long-term delivery applications, the micropump 902 can be head-mounted or implanted. For example, as shown in FIG. 9, the micropump 902 can be contained within a sealed housing and can be implanted in the scalp behind or near the ear.

[0041] The system 900 further includes a cannula 904. The cannula 904 can have a sharp, smooth tip. For example, the tip of the cannula 904 can have a sharpened bevel. The sharp, smooth tip can allow the cannula 904 to pierce the round window membrane 908. In some implementations, the sharp, smooth tip can allow the cannula 904 to pierce the round window membrane 908 without disrupting the membrane 908. The cannula 904 is further described, inter alia, in connection with FIG. 11 .

[0042] 10 shows a top view of an exemplary micropump 902. The micropump 902 may include a drug reservoir 200 and a fluid storage capacitor 1002. A drug-containing fluid may be ejected from the micropump 902 via an outlet 906. The micropump 902 may include a pump 1006. The micropump 902 may include a plurality of valves 208 and a fluid capacitor 1004.

[0043] The micropump 902 may be a multi-layer device. The micropump 902 may include a fluid delivery layer. For example, the fluid delivery layer may include the drug reservoir 200, the fluid storage capacitor 1002, the fluidic capacitor 1004, the channel 1010, and the loading chamber 1012. The micropump 902 may include one or more active layers. The active layer may include actuators for the valves 208 and the pump 1006, a controller for controlling the valves 208 and the pump 1006, and a power source for powering the micropump 902. The fluid delivery layer may be separated from the active layer by a membrane. The fluid delivery layer may include polyetherimide (PEI). The membrane separating the fluid delivery layer from the active layer may include flexible membranes such as polyimide and Viton®.

[0044] The micropump 902 can include a drug reservoir 200. The drug reservoir 200 can be machined (e.g., laser etched) into one or more of the fluid distribution layers. The drug reservoir 200 can be configured as a serpentine channel structure or other channel structure. The drug reservoir 200 can be configured as a channel having an inlet and an outlet such that pumping fluid into the inlet can force the drug out the outlet of the drug reservoir 200 and into one of the channels 1010. The drug reservoir 200 can have a channel width of about 300 μm to about 1200 μm, about 400 μm to about 1000 μm, about 500 μm to about 900 μm, about 600 μm to about 800 μm, or about 700 μm to about 800 μm. Drug reservoir 200 can have a channel height of about 300 μm to about 1200 μm, about 400 μm to about 1000 μm, about 500 μm to about 900 μm, about 600 μm to about 800 μm, or about 700 μm to about 800 μm. Drug reservoir 200 can have a total channel length of about 300 mm to about 100 mm, about 300 mm to about 800 mm, or about 300 mm to about 600 mm.

[0045] The micropump 902 can include a fluid storage capacitor 1002. The fluid storage capacitor 1002 can be a cylinder formed within the fluid delivery layer. The fluid storage capacitor 1002 can have a diameter of about 10 mm to about 20 mm, about 12 mm to about 18 mm, or about 14 mm to about 16 mm. The fluid storage capacitor 1002 can be configured to store fluid withdrawn from the patient's inner ear. The fluid storage capacitor 1002 can also supply fluid to the inlet of the drug reservoir 200 and push the drug out of the outlet of the drug reservoir 200.

[0046] The micropump 902 can also include a plurality of fluidic capacitors 1004. The fluidic capacitors 1004 can be machined to communicate with the fluidic channels 1010 and loading chambers 1012 in the fluid distribution layer. The fluidic capacitors 1004 can have a diameter of about 2 mm to about 10 mm, about 2 mm to about 8 mm, about 2 mm to about 6 mm, or about 4 mm to about 6 mm. The fluidic storage capacitors 1002 and the fluidic capacitors 1004 can have a ceiling formed by a membrane separating the fluid distribution layer from the active layer.

[0047] The fluidic capacitor 1004 can improve power efficiency, help regulate peak flow rates, and store fluid. For example, the channel 1010 of the micropump 902 may have a relatively high fluidic resistance, which can result in a relatively large time constant associated with ejecting fluid from the micropump 902. Therefore, if the time constant is relatively large, the valve 208 may need to be powered for several seconds to open the valve and allow time for the pump chamber to completely drain or fill. The fluidic capacitor 1004 connected to the fluidic channel 1010 has a lower fluidic resistance and can transfer fluid into and out of the pump chamber relatively quickly, after which the fluid flows passively as the pressure in the fluidic capacitor 1004 equilibrates. This can reduce the length of time the valve 208 remains open (to the order of tens of milliseconds), thereby reducing power consumption. A fluidic capacitor 1004, for example a fluidic capacitor 1004 near the outlet 906, can dampen sudden increases in flow rate caused by pump strokes and also suppress large peak flow rates.

[0048] The micropump 902 can include one or more pumps 1006. The pumps 1006 can include an actuator in the active layer of the micropump 902. The actuator can hold an electromagnet in place. When the electromagnet is not powered, a spring can keep the actuator head pressed against the polyimide membrane. Pressure on the polyimide membrane presses the Viton layer against the opening to the cylinder of the valve 1008 formed in the fluidic layer, creating a fluid seal that closes the valve of the pump 1006.

[0049] The actuator of the pump 1006 can be cycled to drain fluid from the fluid chamber of the pump 1006. The valves 1008 can be cycled (e.g., opened and closed) to control the direction of fluid flow through the micropump 902. For example, one valve can act as an intake valve and another valve can act as an exhaust valve for each stroke type. At the start of a pump stroke, the intake valve opens, and then when the pump actuator is powered, fluid is drawn from an adjacent fluidic capacitor into the pump chamber. The intake valve then closes. The exhaust valve then opens, and subsequently when the pump actuator is deactivated, fluid is forced from the pump chamber into a different fluidic capacitor. Finally, the exhaust valve closes. Depending on which valves are selected as the intake and exhaust valves, the pump can generate three different types of pump strokes: injection (e.g., pumping fluid out of the micropump 902), extraction (e.g., pumping fluid into the micropump 902 from an external source), and drug refreshing or priming (e.g., pumping fluid into the loading chamber 1012 and out of the micropump 902 on a final injection stroke).

[0050] The micropump 902 can include one or more valves 1008. The valves 1008 can have a structure similar to the pump 1006. For example, the valves 1008 can include a cylinder chamber formed in a fluidic layer. The valves 1008 can include an actuator in an active layer that holds an electromagnet in place. When the electromagnet is not powered, the valve can be held in a closed position by a spring that presses the actuator against a membrane, forming a seal at the opening of the cylinder chamber of the valve 1008. When the actuator is activated, the electromagnet presses against the spring and away from the membrane, allowing fluid to flow through the valve 1008.

[0051] 11 illustrates an exemplary tip 1100 of cannula 904. Cannula 904 can include tip 1100 and stopper 1102, which may also be referred to in the present disclosure as a bleb 1102. Tip 1100 can include an outlet 1104 that allows fluid to flow into and out of tip 1100 and cannula 904.

[0052] The cannula 904 can comprise multiple different materials. The cannula 904 can comprise multiple separate sections, each of which can comprise a different material. For example, a first section of the cannula 904 can comprise polyetheretherketone (PEEK) tubing. The first section of the cannula 904 can be coupled to the micropump 902. The first section of the cannula 904 can be about 2 cm to about 10 cm, about 2 cm to about 8 cm, or about 3 cm to about 6 cm. The first section of the cannula 904 can have an inner diameter (ID) of about 50 μm to about 300 μm, about 100 μm to about 200 μm, or about 150 μm to about 200 μm.

[0053] The cannula 904 can include a second portion. The second portion can include a tip 1100. The second portion can include polytetrafluoroethylene (PTFE) tubing. The second portion can be about 1 cm to about 5 cm in length, about 2 cm to about 5 cm, or about 3 cm to about 5 cm in length. In some implementations, the first and second portions of the cannula 904 can be joined together by Tygon® tubing. The cannula 904 can be introduced into a patient's cochlea, such as the cochlea 112 shown in FIG. 1 hereinabove, using the handpiece 100. Introducing the cannula 904 into a patient using the handpiece 100 is described in further detail herein below.

[0054] The tip 1100 can have an outer diameter of 10 μm to 200 μm, about 10 μm to about 150 μm, or about 50 μm to about 100 μm. The tip 1100 can have an inner diameter of 5 μm to about 200 μm, about 15 μm to about 150 μm, or about 50 μm to about 110 μm. The tip 1100 can be sufficiently narrow to be fed through one or more channels defined in a portion of the handpiece 100 (e.g., the tool shaft 102, the angled portion 104, or the tip portion 106, etc.).

[0055] The tip 1100 can include a chamfer that allows the tip 1100 to pierce the round window membrane. The angle of the chamfer can be about 10° to about 45°, about 15° to about 45°, or about 25° to about 45°. In some implementations, the chamfer is 30°. The chamfer can form a point or sharp edge that can be used to pierce one or more anatomical structures in a patient's ear.

[0056] The tip 1100 can be inserted (e.g., using the handpiece 100) through the round window membrane 908 so that the tip 1100 of the cannula 904 is immersed in the perilymphatic fluid of the scala tympani. The tip 1100 can have a stiffness (or rigidity) that is significantly greater than that of the body of the cannula 904. The stiffened tip 1100 can facilitate penetration of the round window membrane 908. In some implementations, the cannula 904 is bent at an angle that substantially conforms to the anatomy of the middle ear to facilitate insertion through the round window membrane 908. In some implementations, the bent portion of the cannula 904 can be near the tip 1100.

[0057] The tip 1100 can penetrate several millimeters into the scala tympani. For example, the tip 1100 can penetrate between about 1 mm and about 5 mm, or between about 1 mm and about 3 mm into the scala tympani. The tip 1100 can include a stopper 1102 (also called a bleb 1102) that can prevent the tip 1100 from penetrating too deeply into the scala tympani. For example, the stopper 1102 can be positioned about 3 mm from the end of the tip 1100 such that when the stopper 1102 contacts the round window membrane 908, the tip 1100 is positioned 3 mm into the scala tympani. In some implementations, the stopper 1102 can help form a seal between the cannula 904 and the round window membrane 908 to substantially prevent leakage of fluid from the inner ear.

[0058] The tip 1100 can be coated with a flexible material, similar to silicone, that forms a seal against the round window membrane 908 after insertion through the round window membrane 908. The cannula 904 can be semi-flexible to facilitate insertion through the round window membrane 908 during surgery. The cannula 904 can be locked within the middle ear space to prevent migration of the cannula 904 after implantation.

[0059] The cannula 904 can be coated with a substance that releases anti-inflammatory compounds to suppress otitis media. For example, the cannula 904 can be coated with dexamethasone and / or methylprednisolone. In some implementations, the cannula 904 can remain in place for weeks or months. In other implementations, the cannula 904 can be removed after short-term use.

[0060] 12 illustrates the exemplary handpiece 100 of FIG. 1 together with the exemplary cannula 904 of FIG. 9 in a configuration that may be used to facilitate emplacement of the cannula 904 within a patient's round window membrane. As shown, the cannula 904 may be positioned within a channel defined by the handpiece 100. For example, a user (e.g., a surgeon) may thread the cannula 904 through the handpiece 100 such that a portion of the cannula 904 and a stopper 1102 protrude through the needle end 700 of the handpiece 100. Threading the cannula 904 through one or more channels of the handpiece 100 may enable introduction of the cannula 904 into a patient's anatomical structure, such as the round window membrane of the middle ear. In some implementations, the cannula 904 may be held in place in the needle portion 700 of the handpiece 100 until released by a surgeon or surgical robot. The cannula 904 may be released, for example, once the collar 108 of the handpiece 100 is placed over the patient's round window.

[0061] In some implementations, the materials and dimensions of the handpiece 100 and cannula 904 can be selected to facilitate threading of the cannula 904 through the handpiece 100 to achieve the configuration shown in FIG. 12 . For example, the cannula 904 can be fabricated from a flexible, biocompatible polymer, such as poly(tetrafluoroethylene) (PTFE), which allows the cannula 904 to bend and thread through the handpiece 100. The tubing forming the cannula 904 can have an outer diameter that is smaller than the inner diameter of the channel defined by the handpiece 100. In some implementations, the stopper 1102 can be positioned a predetermined distance from the end of the cannula 904. For example, the predetermined distance can be in a range of about 1 millimeter to about 3 millimeters.

[0062] In operation, the cannula 904 can be threaded through the handpiece 100, which can then be used to pierce the round window membrane. The collar 108 on the end of the handpiece 100 can assist in properly positioning the handpiece 100 within the round window membrane, as described above. After the needle end 700 of the handpiece 100 pierces the round window membrane, the cannula 904 can be pushed out of the needle end 700 of the handpiece 100 and through the round window membrane. The handpiece 100 can then be withdrawn from the middle ear, but the cannula 904 remains behind due to friction between the cannula 904 and the round window membrane. This friction therefore holds the cannula 904 in place within the round window membrane. The cannula 904 can remain in the middle or inner ear even after the handpiece 100 is completely removed from the patient, allowing the handpiece 100 to precisely position the cannula 904 in a desired region of the patient's ear. The stopper 1102 can be used to control the distance the cannula 904 protrudes into the inner ear. In some implementations, the stopper 1102 can be used to control the distance the cannula 904 protrudes into a patient's anatomical structure, such as the cochlea (e.g., cochlea 112 shown in FIG. 1 ). In some implementations, the stopper 1102 can be positioned in the inner ear. In some other implementations, the stopper 1102 can be positioned in the middle ear.

[0063] 13 shows a block diagram of an exemplary method 1300 for infusing fluid into a patient's inner ear. The method may be performed, for example, by a surgeon using a handpiece (such as the handpiece 100 described herein) or by a surgical robot using the handpiece. The method 1300 may include introducing a cannula into a channel of the handpiece (block 1302). The method 1300 may include piercing a round window membrane of the patient (block 1304). The method 1300 may include implanting the cannula into the patient via the handpiece (block 1306). The method 1300 may include placing a stopper in the round window (block 1308). The method 1300 may include withdrawing the handpiece from the patient's ear (block 1310).

[0064] The method 1300 may include introducing a cannula (e.g., cannula 904, etc.) into a channel of a hand piece (block 1302). Referring also to FIGS. 9-12 , the cannula may be cannula 904, and the hand piece may be hand piece 100, as described above. The cannula 904 may be formed from a flexible material, such as PTFE, that allows the cannula 904 to be manipulated into the channel of the hand piece 100. In some implementations, the cannula 904 may be threaded into the channel of the hand piece 100. The cannula 904 may be inserted into the channel a distance that allows an end of the cannula 904 to be positioned at or near the exit of the channel of the hand piece 100 (e.g., at or near the distal end of the hand piece 100). In some implementations, the cannula 904 may protrude from the needle portion 700 of the hand piece 100 (e.g., as shown in FIG. 12 ). In some implementations, the cannula 904 can remain within the needle portion 700 of the handpiece 100 until the handpiece 100 is properly positioned in the patient's anatomical structure (e.g., the round window or middle ear, etc.).

[0065] The method 1300 may include piercing a round window membrane or another anatomical structure in the patient's middle or inner ear (block 1304). In some implementations, the round window membrane or other anatomical structure may be pierced by the distal end of the hand piece 100. For example, the prepared hand piece 100 may be inserted through an ear canal (such as the ear canal 110 shown in FIG. 1 ). The cannula 904 may remain within the channel of the hand piece 100 while the hand piece 100 is inserted. The angled portion 104 of the hand piece 100 may be configured to access the round window through the ear canal. The tip 500 of the distal end portion 106 may be angled so that the needle end 700 is positioned substantially perpendicular to the round window and the round window membrane or another anatomical structure in the patient's ear. The needle end 700 may be pressed against the round window membrane to pierce the membrane. In some implementations, the needle end 700 can be pressed against another anatomical structure in the patient's ear to puncture the anatomical structure. The collar 108 can prevent the needle end 700 from protruding too far into the cochlea or other inner ear organ or anatomical structure and damaging the cochlea or other anatomical structure. However, the collar 108 can allow the needle end 700 to protrude into the round window membrane or other anatomical structure far enough to introduce and secure the cannula 904 to the patient.

[0066] The collar 108 can rest against the round window or another anatomical structure in the patient's ear to seal the round window when fluid is being infused into the cochlea. Depending on the patient's anatomy, the surgeon can set a rotational offset between the tip portion and the angled portion of the handpiece 100 to allow access of the needle end 700 to the round window. Furthermore, depending on the patient's anatomy, the surgeon can set the angle 210 between the needle end 700 and the tip portion so that the outlet 304 is positioned substantially perpendicular to the round window and the round window membrane. CT or MRI scans of the patient's middle and inner ear can also be performed. The surgeon can measure the anatomical angles of the patient's inner and middle ear to select the angle 210 of the tip portion 106. Furthermore, based on the CT or MRI scan, the surgeon can select the length of the needle end 700 so that the outlet 304 is properly positioned within the cochlea when the collar 108 is placed within the round window. A suitable location for the outlet 304 may be at a depth within the cochlea that allows for distribution of fluid into the cochlea without damaging the cochlea.

[0067] The method 1300 can include implanting a cannula into the patient via the handpiece (block 1306). The cannula 904 can be implanted through the outlet of the handpiece 100. For example, the cannula 904 can be pushed out of the needle end 700 of the handpiece 100 used to puncture the round window membrane and inserted through the membrane. In some implementations, the length of insertion of the cannula 904 can be controlled based on the position of the stopper 1102. Alternatively, the cannula 904 can be inserted manually without the use of the handpiece 100. For example, the cannula 904 can be inserted after puncturing the round window membrane using a separate tool, or the cannula 904 itself can be used to puncture the round window membrane. However, such an approach can be difficult to perform or require invasive medical procedures to visualize and spatially access the middle ear. Additionally, the handpiece 100 itself may be usable to administer drugs or other therapeutic substances without the use of a cannula. However, doing so would likely be unsuitable for long-term drug delivery. The use of a cannula and handpiece in combination addresses both of these technical challenges.

[0068] The method 1300 may include placing a stopper within the round window (block 1308). Specifically, with reference to FIG. 11 , the cannula 904 may include a stopper 1102. The stopper 1102 may be conical and configured to rest within the round window or the perforation in the round window membrane created by the tip 1100. By placing the stopper 1102 within the round window membrane, the tip 1100 can protrude a predetermined length into the inner ear. In some other implementations, the cannula 904 does not include a stopper 1102, and once the tip 1100 has pierced the round window membrane, the cannula 904 may be held in place by a silicone-based glue.

[0069] The method 1300 may include removing the handpiece 100 from the patient's ear (block 1310). The handpiece 100 may be removed carefully so as not to disturb the implanted cannula. Thus, the cannula may be left behind when the handpiece 100 is removed. The cannula 904 may remain permanently or semi-permanently within the inner ear. As described hereinabove, the cannula 904 may be placed within the round window membrane or another anatomical structure within the patient's ear. In some implementations, the cannula 904 may be placed within the patient's middle ear. In some implementations, the cannula 904 may be placed within the patient's inner ear. A portion of the cannula 904 (e.g., the tip 1100 having the outlet 1104) may extend into an anatomical organ or structure within the inner ear, such as the cochlea (e.g., the cochlea 112 shown in FIG. 1).

[0070] The cannula 904 may be adapted for long-term drug delivery. For example, the cannula 904 may remain implanted in the patient for an extended period of time. In some implementations, the method 1300 may further include implanting a micropump in the patient. Referring also to FIGS. 9-11 , the micropump may be the micropump 902 shown in FIGS. 9 and 10 . Implanting the micropump 902 may include performing a further surgical procedure to implant the micropump in a region near the patient's skull, as illustrated in FIG. 9 . Implanting the micropump 902 may include coupling the micropump to a microchannel in fluid communication with the outlet 1104 at the tip 1100 of the cannula 904. Thus, the micropump 902 may pump fluid, such as fluid from a drug reservoir, through the microchannel and the cannula 904 and into the cochlea or other organs in the patient's inner ear. The micropump 902 and cannula 904 can be permanently or semi-permanently implanted, allowing for continuous or long-term drug delivery.

[0071] The micropump 902 may include a drug reservoir 200 for storing a drug or other fluid to be infused into the patient's inner ear. The micropump 902 may include a fluid storage capacitor 1002. After infusing the fluid into the inner ear, the micropump 902 may withdraw the fluid from the inner ear and store the fluid in the fluid storage capacitor 1002 so that the net fluid displacement resulting from the injection by the micropump 902 is substantially zero over a single cycle including the injection and withdrawal phases. The micropump 902 may include a pump 1006 capable of pumping fluid from the drug reservoir 200 into the inner ear and withdrawing fluid from the inner ear for storage in the fluid storage capacitor 1002. Maintaining a net fluid displacement of approximately zero may prevent excess pressure buildup within the inner ear and potential damage to anatomical structures within the inner ear.

[0072] In some implementations, the method 1300 can include flushing fluid into the inner ear. Flushing the fluid into the inner ear can include priming the micropump 902, injecting the fluid into the inner ear, and then withdrawing the fluid from the inner ear. For example, to prime the micropump 902, a first valve 1008 coupled to a first end of the drug reservoir 200 can be opened, and the pump 1006 can be activated to withdraw drug-containing fluid from the drug reservoir 200 into a loading chamber coupled to the outlet 906. Once the first valve 1008 is closed, a second valve 1008 coupled to a second end of the drug reservoir 200 can be opened to allow fluid previously in the loading chamber (to be drained by the drug-containing fluid) to enter the opposite end of the drug reservoir 200 from which the drug-containing fluid was withdrawn. To infuse the drug-containing fluid into the inner ear, fluid can be pumped from the fluid storage capacitor 1002 toward the outlet 906, which forces the drug-containing fluid in the loading chamber out the outlet 906. After allowing the drug to diffuse within the inner ear for a period of time, the micropump 902 can extract a volume of fluid from the cochlea. The extracted volume can be substantially the same volume as the volume of drug injected into the cochlea. In some implementations, when the level of the compound in the drug reservoir 200 falls below a predetermined level, additional compound or drug can be introduced into the drug reservoir 200 from an external reservoir.

[0073] The above method may be used to inject large or lipophobic compounds that may not be suitable for delivery to the inner ear by other methods. For example, other methods can deliver these compounds to the inner ear by placing them in a liquid or gel formulation. The formulation can then be placed on the round window membrane. The compound can enter the cochlea by passive transport through the round window membrane. This transport mechanism may be ineffective for large or lipophobic drugs, which can only cross the round window membrane by a slow active transport mechanism. Furthermore, the pharmacokinetics of transround window membrane delivery can be difficult to predict. Furthermore, round window membrane delivery can result in uneven distribution of the drug throughout the inner ear and insufficient drug bioavailability within the cochlea. To compensate for uneven distribution and low drug levels within the cochlea, large amounts of drug are delivered into the middle ear, which can potentially cause local toxicity. The method using the transround window membrane drug delivery system 900 may enable the use of a wider variety of compounds, including large molecules and lipophobic compounds. The method may directly access the perilymphatic fluid of the cochlea, which may allow for a more uniform distribution of the compound within the inner ear. Because the compound is distributed directly and uniformly within the inner ear, less drug may be required, providing a distinct improvement over other wasteful techniques.

[0074] Figures 14 and 15 show PK (Figure 14) and PD (Figure 15) plots for different delivery methods. Drugs were administered to the inner ear of guinea pigs. The guinea pigs were divided into three different groups. Drugs were administered to the different groups of guinea pigs by different administration methods. The first administration method involved intratympanic injection (IT). The second administration method involved inserting a cannula into the inner ear via cochleostomy. The third administration method involved inserting a cannula into the inner ear via the round window membrane. The third administration method, the transround window membrane method, is similar to the method described above in connection with Figure 13.

[0075] For the cochleostomy and transround window membrane experiments, 0.35 μg of drug was infused into the inner ear. For the IT experiments, 50 μg of drug was infused into the inner ear. Referring to FIG. 14 , plot 1400 shows the PK normalized to the total mass of drug injected for cochleostomy versus IT injection. Plot 1402 shows the PK normalized to the total mass of drug injected for transround window membrane versus IT injection. As shown in plots 1400 and 1402, PK was highest for experiments in which the drug was infused using a micropump in a manner similar to that described above in connection with FIG. 13 . Referring to FIG. 15 , plot 1500 shows the PD normalized to the total mass of drug injected for cochleostomy versus IT injection. Plot 1502 shows the PD normalized to the total mass of drug infused for drug infused via the round window membrane approach versus IT injection. As shown in plots 1500 and 1502, the PD was highest for experiments in which the drug was infused using a micropump in a manner similar to that described above in connection with FIG.

[0076] Although the figures illustrate operations in a particular order, such operations do not have to be performed in the particular order or sequence shown, nor do all of the operations shown have to be performed. Acts described herein may also be performed in different orders.

[0077] The separation of various system components does not require separation in all implementations, and the components of the described programs may be incorporated into a single hardware or software product.

[0078] Although several exemplary implementations have been described herein, it should be apparent that the foregoing is illustrative, not limiting, and is provided by way of example. In particular, while many of the examples presented herein include particular combinations of method acts or system elements, such method acts and system elements may be combined in other ways to achieve the same purpose. Acts, elements, and features discussed in connection with one implementation are not intended to be excluded from a similar role in other implementations.

[0079] The phraseology and terminology used herein are for purposes of description and should not be considered limiting. The use of "including," "comprising," "having," "containing," "including," "featuring," and variations thereof is meant to encompass the subsequently listed items, equivalents thereof, and additional items, as well as alternative implementations consisting only of the subsequently listed items. In one implementation, the systems and methods described herein consist of one, each combination of one or more, or all of the listed elements, acts, or components.

[0080] As used herein, the terms "about" and "substantially" will be understood by one of ordinary skill in the art and will vary to some extent depending on the context in which the term is used. If there is any use of a term that is not clear to a person of ordinary skill in the art given the context in which the term is used, "about" will mean up to plus or minus 10% of the particular term.

[0081] Any reference herein to system and method implementations or elements or acts in the singular may also encompass implementations that include a plurality of such elements, and any reference herein to any implementation or element or act in the plural may also encompass implementations that include only a single element. References in the singular or plural are not intended to limit the systems or methods disclosed herein, their components, acts, or elements, to a single configuration or to multiple configurations. References to any act or element being based on any information, act, or element may include implementations in which the act or element is based at least in part on any information, act, or element.

[0082] The implementations disclosed herein may be combined with any other implementations or embodiments, and references to "an implementation," "some implementations," or "an implementation" are not necessarily mutually exclusive and are intended to indicate that a particular feature, structure, or characteristic described in connection with that implementation may be included in at least one implementation or embodiment. Such terms as used herein do not necessarily all refer to the same implementation. Any implementation may be combined with any other implementation, inclusively or exclusively, in any manner consistent with the aspects and implementations disclosed herein.

[0083] The indefinite articles "a" and "one," as used in this specification and claims, unless expressly stated otherwise, should be understood to mean "at least one."

[0084] References to "or" may be construed as inclusive, such that any term listed with "or" may refer to any one, more than one, or all of the listed terms. For example, a reference to "at least one" of "A" and "B" may include reference to only "A," only "B," and both "A" and "B." Such references, when used with "comprising" or other open terminology, may include additional things.

[0085] When a reference sign follows a technical feature contained in a drawing, the detailed description, or any claim, the reference sign is included to enhance the comprehension of the drawing, the detailed description, and the claim, and therefore, the presence or absence of the reference sign in no way imposes a limitation on the scope of any claim element.

[0086] The systems and methods described herein may be embodied in other specific forms without departing from the characteristics of these systems and methods. The above implementations are intended to be illustrative rather than limiting of the described systems and methods. Accordingly, the scope of the systems and methods described herein is indicated by the appended claims, rather than the above description, and all changes that come within the meaning and range of the claims are intended to be encompassed therein.

Claims

1. a cannula having a first end coupled to the micropump and a second end having a stopper configured to allow insertion of the tip of the cannula through the patient's round window membrane and into the patient's cochlea; a handpiece configured to introduce the cannula into the patient, a channel defined by a tool shaft of the handpiece and configured to receive the cannula; a tip portion coupled to the tool shaft and having an outlet in communication with the channel, the tip portion configured to pierce a round window membrane of the patient; and a collar coupled to the tip portion a predetermined distance from the outlet, the collar configured to rest in the patient's inner ear and to control the distance the tip portion can protrude into the patient's cochlea. a handpiece comprising: A system comprising: the handpiece is configured to be withdrawn from the patient's ear in response to placing the cannula within the patient's inner ear; A stopper on the cannula is configured to retain the cannula within the patient's inner ear by friction when the handpiece is withdrawn.

2. 10. The system of claim 1, wherein the micropump is configured for implantation in a patient, the micropump comprising a drug reservoir containing a compound.

3. 3. The system of claim 2, wherein the micropump is further configured to pump the compound from the drug reservoir through the cannula and into the patient's cochlea.

4. 4. The system of claim 3, wherein the micropump is further configured to withdraw a predetermined volume of fluid from the patient's cochlea in response to pumping the compound from the drug reservoir through the cannula and into the cochlea.

5. 4. The system of claim 3, wherein the micropump further comprises a first valve, a second valve, a pump, a loading chamber, and an outlet in fluid communication with the cannula, the micropump comprising: drawing the compound from the drug reservoir into the loading chamber by opening the first valve and activating the pump; The compound is forced through the outlet of the cannula by closing the first valve, opening the second valve, and activating the pump. The system is configured as follows.

6. 10. The system of claim 1, wherein the handpiece further comprises an angled portion connecting the tip portion to the tool shaft, the angled portion having a second channel in communication with the channel and an outlet of the tip portion.

7. 7. The system of claim 6, wherein at least one of the angled portion or the tip portion is separable from the tool shaft and can be joined together using one or more of a snap connector, a friction fit connection, a press fit connection, a knurled nut, or a luer lock connection.

8. 7. The system of claim 6, wherein the angled portion, the tip portion, and the tool shaft are fabricated from a single, continuous piece of material comprising at least one of stainless steel or plastic.

9. 7. The system of claim 6, wherein at least one of the angled portion or the tip portion can rotate about an axis parallel to the length of the tool shaft while remaining coupled to the tool shaft.

10. 10. The system of claim 1, wherein the distal portion of the handpiece further comprises a needle tip, the needle tip configured to pierce a round window membrane of the patient.

11. 10. The system of claim 1, wherein the outlet of the tip section is positioned at a distal end of the tip section, the distal end of the tip section forming an angle between the outlet and the tip section, the angle being between 70° and 170°, between 75° and 130°, between 90° and 120°, or between 110° and 120°.

12. The system of claim 1 , wherein the tool shaft has a length between 130 mm and 170 mm, between 140 mm and 160 mm, or between 140 mm and 150 mm.

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