WO2011057065A1

WO2011057065A1 - Apparatuses and methods for delivering substances to the inner eye

Info

Publication number: WO2011057065A1
Application number: PCT/US2010/055609
Authority: WO
Inventors: Paul Gamlin; Clark D. Witherspoon; John Alexander
Original assignee: The Uab Research Foundation
Priority date: 2009-11-06
Filing date: 2010-11-05
Publication date: 2011-05-12

Abstract

Apparatus and methods for delivering substances to the inner eye. In one embodiment, the apparatus includes a handheld injection device having a body including a housing and a chamber adapted to receive a disposable cartridge that contains a liquid substance to be injected, a drive mechanism contained within the housing adapted to drive the fluid substance contained in the cartridge out of the cartridge and into a cannula associated with the cartridge, and a central control unit contained within the housing that controls operation of the drive mechanism.

Description

APPARATUSES AND METHODS FOR DELIVERING

SUBSTANCES TO THE INNER EYE

BACKGROUND

Recent studies in humans have documented the value and efficacy of gene therapy for the treatment of retinal diseases/dysfunction. In the studies, therapeutic genes were delivered to the outer retina using adeno-associated virus (AAV) vectors. It can be challenging, however, to effectively deliver such substances to the inner retina. Specifically, primates, including humans, possess a robust barrier in the form of the inner limiting membrane (ILM) that prevents substances from invading the retina from the vitreous. The ILM significantly restricts the movement of substances from the vitreous into the retina, particularly those greater than 76 kiloDaltons (kD). It can therefore be appreciated that it would be desirable to have an apparatus and method for delivering substances, such as AAV vectors, to the inner and outer retina.

BRIEF DESCRIPTION OF THE DRAWINGS

The disclosed apparatuses and methods can be better understood with reference to the following drawings. The components in the drawings are not necessarily drawn to scale.

FIG. 1 A is side view of an embodiment of a handheld injection device.

FIG. 1B is a partial cross-sectional side view of the injection device of FIG. 1A. FIG. 2A is a side view of an embodiment of a cartridge that can be used with the injection device of FIGs. 1A and 1 B.

FIG. 2B is a side view of an alternative plunger that can be used with the cartridge of FIG. 2A.

FIG. 3 is a side view of an embodiment of a distal end of a cannula that can be used with the injection device of FIGs. 1A and 1 B.

FIG. 4 is a partial cross-sectional view of the cannula of FIG. 3 taken along line

4-4.

FIG. 5A is a partial top view of an embodiment of the tip of the cannula of FIG. 3. FIG. 5B is a partial side view of the cannula tip of FIG. 5A.

FIGs. 6A-6E are schematic side views of the eye that illustrate a sequence of an example procedure performed using a handheld injection device.

FIG. 7 is a schematic side view of the eye that illustrates a further example procedure performed using a handheld injection device.

DETAILED DESCRIPTION

As described above, it would be desirable to have an apparatus and method for delivering substances in very specific volumes to the inner or outer retina. Disclosed herein are injection devices that are specifically designed for that purpose. In some embodiments, the device is configured as a microprocessor-controlled, handheld injection device that is capable of delivering precise amounts of a liquid substance to the retina using a unique cannula having a curved, tapered, and flattened distal end. The device can be used to inject substances within the retina beneath the inner limiting membrane (ILM), as well as beneath the retina, such as the subretinal space. In the following disclosure, various embodiments are described. It is to be understood that those embodiments are merely example implementations of the disclosed inventions. Accordingly, Applicant does not intend to limit the present disclosure to those particular embodiments. Although the discussion that follows focuses on the injection of substances within or below the retina, it is noted that those applications are only cited as examples for purpose of convenience in describing the disclosed devices, which can be used for other purposes.

FIGs. 1A and 1 B illustrate an example embodiment of a handheld injection device 10 that can be used to deliver substances to the inner eye. Beginning with FIG. 1A, which illustrates the exterior of the device 10, the device generally comprises an elongated body 12 having a proximal end 14 and a distal end 16. The body 12 further includes an outer housing 18, which is sealed to prevent the ingress of fluids (air and/or liquids) and to facilitate sterilization. In some embodiments, the housing 18 is economically contoured to fit the hand of an operating surgeon. In such a case, the housing 18 can comprise a central bulbous portion 20 that is adjacent to a proximal neck portion 22 and a distal neck portion 24.

The body 12 can include various user interface components. In the example embodiment of FIG. 1A, those components include user input controls in the form of one or more buttons 26 and user signaling devices in the form of one or more light indicators 28 (e.g., light emitting diodes (LEDs)) and a speaker 30. The purpose and operation of the user interface components will be discussed later in this disclosure.

Connected to the body 12 of the handheld injection device 10 is a cartridge 32 that contains the substance that is to be delivered to the eye. Connected to or forming part of the cartridge 32 is a needle or cannula 34. Both the cartridge 32 and the cannula 34 will be described in greater detail below.

FIG. 1 B schematically illustrates the interior 36 of the injection device body 12 as well as various components that can be contained within the sealed device housing 18. In the example of FIG. 1 B, those components include a central control unit 38, a wireless receiver 40, a drive mechanism 42, a power source 44, and a recharging component 46. The control unit 38 can comprise a microprocessor and associated memory that is configured to control the operation of the injection device 10 responsive to commands received from the user. The wireless receiver 40 is adapted to receive wireless (e.g., radio frequency (RF)) commands that are transmitted by the user. In some embodiments, the commands can be input using a foot pedal (not shown) equipped with a suitable wireless transmitter. In some embodiments, commands can be input using the user input controls provided on the device body 12 or by physically coupling the injection device 10 to another device, such as a computer, using a cable (not shown).

The central control unit 38 controls operation of the drive mechanism 42, which is used to automatically drive a substance contained within the cartridge 32 out through the cannula 34 and into an injection site. In some embodiments, the drive mechanism 42 comprises a screw-type drive mechanism that includes a threaded member or rod 48 that can be linearly extended with fine control through operation of an internal motor and gear system. Because very precise extension is possible with such a configuration, the drive mechanism 42 can be used to deliver very precise amounts of substance from the cartridge 32.

The power source 44 powers the central control unit 38, the wireless receiver 40, and the drive mechanism 42. In some embodiments, the power source 44 comprises a rechargeable battery, such as a nickel-cadmium (NiCd) battery, a nickel-metal hydride (NiMH) battery, a lithium-ion battery, or a lithium-ion polymer battery. The recharging component 46 is used to recharge the power source 44. In some embodiments, the recharging component 46 comprises an inductive charging component that does not require physical contact with electrical conductors, thereby maintaining the seal of the housing 18. In such a case, the injection device 10 can be recharged by, for example, docking the device in a recharging base unit (not shown). In other embodiments, however, recharging can be performed using a power cable. Moreover, in other embodiments the power source 44 can be a non- rechargeable, and therefore replaceable, battery.

As shown in FIG. 1 B, the cartridge 32 is inserted into the body 12 of the handheld injection device 10 before use. The cartridge 32 can be received within a chamber 50 that securely holds the cartridge in place. That security can be provided by one or more locking elements (not shown) such as detents, clips, screw threads, a bayonet fitting, a friction fitting, or the like.

An example embodiment for the cartridge 32 is illustrated in FIG. 2A. As shown in that figure, the cartridge 32 can comprise an elongated, generally cylindrical tube 52 that preferably is made of a transparent material, such as clear glass or plastic. The tube 52 has a proximal end 54, a distal end 56, and defines an interior space 58 in which the substance to be delivered is contained. In some embodiments, the cartridge 32 comprises a single-use, disposal cartridge that comes prefilled with a particular volume of a particular liquid substance. Regardless, the cartridge 32 is designed to minimize dead space and waste of expensive injectable substances. The substance contained in the cartridge can comprise any substance that is suitable for injection. In some embodiments, the substance comprises a therapeutic or diagnostic agent that is suspended in a suitable sterile liquid. Example agents include adeno-associated virus (AAV) vectors (and other viral and non-viral vectors), antibodies, proteins, drugs, enzymes, cells (such as stem cells), growth factors, nanoparticles, chemotherapeutic compounds, radioactive compounds, nanoelectronic devices, imaging contrast agents, quantum dots, and vitamins. Example liquids include sodium hyaluronate, balanced salt solutions (such as Alcon's BSS® and BSS+®), normal saline, lactated ringers, and growth media.

Also provided within the interior space 58 of the cartridge 32 is a plunger 60 that is configured to be urged along the interior space toward the distal end 56 of the tube 52 (see arrow 62 and phantom plunger 64) to expel the substance to be injected. In the illustrated embodiment, the plunger 60 comprises a body 66 and one or more resilient seals 68 that are pressed into firm contact with the inner walls of the tube 52. The proximal end of the plunger body 66 includes a surface 70 that is engaged by the rod 48 of the drive mechanism 42 when a substance is delivered by the injection device 10.

FIG. 2B illustrates an alternative plunger 60' that can be used with the cartridge 32. The plunger 60' is similar in many ways to the plunger 60 of FIG. 2A except that it includes a threaded aperture 65 that is adapted to receive a threaded screw 67, which may be formed as a hex-head screw. The screw 67 can be threaded into the body 66 of the plunger 60' with a conical gasket 69 or other sealing member positioned between the screw and the body. With such a configuration, the screw 67 can be removed in order to facilitate filling of the interior space 58 via the aperture 65 prior to performing an injection procedure, and then securely threaded back in place. With reference back to FIG. 2A, the cartridge 32 can be provided with an identification element 71 that contains information regarding the type and volume of substance the cartridge contains and the type of cannula 34 that is attached to the cartridge. By way of example, the element 71 comprises a small random access memory (RAM) or read only memory (ROM) chip that can be interrogated by an appropriate reading element (not shown) provided in the body 12 of the injection device 0.

Provided at the distal end 56 of the cartridge 32 is the cannula 34. In some embodiments, the cannula 34 is permanently affixed to the tube 52, in which case the cannula can be considered to be part of the cartridge 32. In other embodiments, the cannula 34 comprises an independent component that can be attached to the cartridge 32, for instance using a coupling 72. Regardless, the cannula 34 placed is in fluid communication with the interior space 58 of the cartridge 32 when substance is delivered by the injection device 10. In some embodiments, the cartridge 32 includes an internal barrier (not shown), such as a thin membrane, that prevents the substance contained within the interior space 58 from accidentally flowing into the cannula 34. Such a barrier can be pierced or ruptured to enable substance flow just prior to performing an injection procedure.

With reference back to FIGs. 1A and 1 B, it can be appreciated that the cannula 34 comprises an elongated straight shaft 74 that extends from the cartridge 32 and a curved distal end 76. In some embodiments, the straight shaft 74 and the curved distal end 76 are unitarily formed from the same material, such as surgical steel. In other embodiments, they can comprise different components. In the latter case, the straight shaft 74 can be composed of steel and the curved distal end 76 can be composed one or more of a glass, polymer, or composite material. Regardless, the straight shaft 76 can range from approximately 20 gauge to 25 gauge and can be approximately 15 millimeters (mm) to 35 mm long.

FIG. 3 illustrates an example embodiment for the distal end 76 of the cannula 34. As shown in that figure, the distal end 76 curves away from the straight shaft 74 of the cannula 34 such that a dissection tip 78 of the distal end faces a direction that is substantially perpendicular to the longitudinal axis of the straight shaft. In some embodiments, at least a portion of the distal end 76 has a radius of curvature, R, that approximates the radius of curvature of the human retina. Accordingly, the distal end 76 can comprise a radius of curvature of approximately 10 mm to 30 mm. The distal end 76 of the cannula 34 is also tapered such that it begins with the same general dimensions of the straight shaft 74 but quickly reduces in size toward the tip 78. In some embodiments, that taper occurs along the entire length of the distal end 76, which can be approximately 2 mm to 4 mm in length.

In addition to being curved and tapered, the distal end 76 of the cannula 34 is further elliptical in cross-section. This configuration can be best seen in the cross- section of FIG. 4, which is taken along line 4-4 in FIG. 3. As shown in FIG. 4, the distal end 76 of the cannula 34 has a larger width dimension, W, than height dimension, H, so that the cannula has a flattened cross-section that facilitates entry and dissection of the retina. In some embodiments, the width ranges from 60 microns (pm) to 150 pm and the height ranges from 30 pm to 120 pm at the dissection tip 78 (roughly the equivalent of 40-42 gauge). Further illustrated in FIG. 4 is the internal passage 80 formed by the cannula 34.

FIGs. 5A and 5B illustrate an example embodiment for the dissection tip 78 of the distal end 76 of the cannula 34. As shown in FIG. 5A, the tip 78 includes an aperture 82 through which a substance is ejected during use of the injection device 10. The aperture 82 is defined by a continuous outer edge that comprises various discrete portions, including opposed, substantially straight leading edges 84 and opposed substantially straight medial edges 86. The leading edges 84 are very sharp and angled relative to each other so as to form a pointed cutting blade 88 that can be used to initially pierce the ILM. As is illustrated in FIG. 5B, the blade 88 can form a substantially planar lip. Referring back to FIG. 5A, the medial edges 86 are semi- sharp and extend outwardly and proximally from the leading edges 84 so as to be configured to widen the opening in the ILM formed by the cutting blade 88. The aperture 82 is further defined by opposed substantially straight trailing edges 90 that extend inwardly and proximally from the medial edges 86, and by a curved rearmost edge 92 that extends between the trailing edges. As is illustrated in FIG. 5B, the aperture 82 is a beveled aperture such that the tip 78 narrows from the rearmost edge 92 to the cutting blade 88. The aforementioned taper is also apparent from both FIGs. 5A and 5B. In some embodiments, a plug (not shown) can be provided within the internal passage 80 of the cannula 34 near the tip 78 to prevent substance contained in the cannula from leaking out prior to the injection procedure. Alternatively, a cap (not shown) can be provided over the tip 78 to serve the same purpose and to protect the tip from damage.

Various features of example embodiments having been discussed above, use of the handheld injection device 10 will now be discussed. Prior to performing an injection procedure, the handheld injection device 10 must be prepared for use. Such preparation includes selection of a cartridge 32 that is appropriate for the particular procedure that is to be performed. Therefore, a cartridge 32 that contains the correct volume of the particular substance that is to be injected is selected. Notably, selection of the cartridge 32 can comprise selection of the cartridge that has the desired type and/or size cannula 34. When the cannula 34 is separate from the cartridge 32, it may be separately selected and then attached to the cartridge.

Once the cartridge 32 and cannula 34 have been selected, the cartridge can be inserted into the chamber 50 of the body 12 of the injection device 10 and locked in place. At this point, steps can be performed to enable fluid to be ejected from the cannula 34. For instance, if the cartridge 32 comprises an internal barrier that prevents the substance contained within the interior space 58 from flowing into the cannula 34, the barrier can be pierced by a suitable piercing element (e.g., a sharp tip associated with the cannula) or ruptured (e.g., a sharp tip through operation of the drive mechanism 42). Alternatively, any plug or cap provided at the tip 78 of the cannula 34 can be removed.

Either before or after the cartridge 32 has been inserted into the injection device 10, the device can be turned on, for instance using a button 26 provided on the body 12. If the cartridge 32 is provided with an identification element 71 , the central control unit 38 can read the identification element and determine what substance the cartridge contains and which cannula the cartridge comprises. This information can be useful as both the viscosity of the substance and the dimensions of the cannula 34 have an affect on the flow rate of the substance from the cannula and into the injection site. In some embodiments, the central control unit 38 stores multiple preset injection routines that are particular to the substance and/or cannula 34 and that modulate the drive mechanism 42 to achieve a particular flow rate as a function of time. In addition, the routines can be dependent on other factors, such as the type of procedure being performed and/or the particular volume of injection that is desired. In some embodiments, the preset injection routines can be automatically selected by the central control unit 38 responsive to reading the identification element 71. In addition or in exception, the user can manually select a given preset injection routine using one of the buttons 26 or a separate device (e.g., computer) that is coupled to the injection device 10.

After all preparatory measures have been completed, the injection procedure can be performed. FIGs. 6A-6E show steps in an example procedure to inject a substance into the retina of an eye 94. With reference first to FIG. 6A, a sclerotomy or port 96 can be established through the sclera 98 adjacent to the iris 100 to provide access to the interior of the eye 94. Notably, other ports (not shown) can be provided through the sclera 98 for purposes of illumination and irrigation. Once sclerotomy (or port 96) has been established, the cannula 34 can be passed through the sclera 98 and into the vitreous 102, as shown in FIG. 6A. As indicated in that figure, the cannula 34 may need to be tilted in order to pass the curved distal end 76 of the cannula through the sclerotomy or port 96. After the distal end 76 has entered the vitreous 102, the cannula 34 can be inserted deeply into the eye 94 toward the retina 104, as indicated in FIG. 6B. The movement and position of the cannula 34 within the eye 94 can be observed at all times during the procedure using a surgical microscope.

Referring next to FIG. 6C, the tip 78 of the cannula 34 is positioned adjacent the ILM 106 of the retina 104 at a desired point of entry. In this example, the point of entry is near the macula 108. The cutting blade 88 (FIGs. 5A and 5B) of the tip 78 can be used to pierce the ILM 106 to access the interior of the retina 104, as indicated in FIG. 6D. As indicated in that figure, the cannula 34 passes into the retina in close proximity to the underside of the IL 106 so as to form a dissection plane substantially parallel to the ILM. Due to the taper of the cannula 34, the opening formed in the ILM 106 is gently dilated as the cannula tip is passed through the ILM, thereby ensuring a good seal between the ILM and the cannula.

Once the cannula tip 78 is in the correct position, the substance contained within the cartridge 32 can be injected into the retina 104. In some embodiments, such injection is initiated by the surgeon using a control separate from the injection device 10 to avoid unwanted movement of the device. By way of example, the surgeon can activate a switch using a foot pedal and an "initiate injection sequence" command can be wirelessly transmitted (or transmitted by wire) to the injection device 10. Once that command is received by the central control unit 38, the unit can activate the drive mechanism 42 to eject the substance from the cartridge 32 and the cannula 34. As mentioned above, the flow rates can be controlled by the central control unit 38 relative to various factors, such as the substance being injected, the cannula 34 being used, the procedure being performed, the desired volume to be injected, and so forth. In addition, the central control unit 38 can control the flow rate such that an initial burst of substance is injected under the ILM 104, to provide local separation of the ILM from the remainder of the retina 04 and thereafter reduce the flow rate as appropriate. In some embodiments, feedback can be provided to the surgeon or the surgeon's assistant during injection. For example, the speaker 30 (FIG. 1) can be used to provide audible indications as to operation of the injection device, the flow rate, the current stage of the procedure, the volume of substance that has been injected, and the like. In similar manner, the light indicators 28 (FIG. 1) can be used to convey the same or similar information.

With reference to FIG. 6E, a blister-like reservoir 110 of substance forms between the ILM 106 and the nerve fiber layer 112 of the retina 104. The ILM 106 serves to confine the substance within that reservoir 110 so that the substance does not migrate to other areas of the eye 94. In some embodiments the central control unit 38 halts injection after a predetermined volume of substance has been injected. In addition or exception, the surgeon can manually halt the delivery of the substance to the injection site, for example using the foot pedal. By way of example, approximately 5 microliters (μΙ) to 100 μΙ of substance can be injected to form a reservoir 110 that is approximately 2 mm to 15 mm in diameter. These parameters will vary depending on the location and type of injection and substances to be injected. Irrespective of the amount of substance that is delivered, once the desired amount of substance has been injected, the cannula 34 can be removed from the eye 94.

FIG. 7 illustrates a further example injection procedure. This procedure is similar to the procedure described above in relation to FIGs. 6A-6E except that, as indicated in FIG. 7, the cannula 34 is used to inject the substance underneath the retina 104.

Although various embodiments have bee discussed in the present disclosure, many variations of those embodiments are possible. For example, in one variation, one or more of the components contained within the body of the handheld injection device can be provided in a separate device that is coupled to or at least in communication with the injection device.

Claims

Claimed are:

1. A handheld injection device comprising:

a body including a housing and a chamber adapted to receive a disposable cartridge that contains a liquid substance to be injected;

a drive mechanism contained within the housing adapted to drive the fluid substance contained in the cartridge out of the cartridge and into a cannula associated with the cartridge; and

a central control unit contained within the housing that controls operation of the drive mechanism.

2. The injection device of claim 1 , wherein the housing is economically designed to fit within a hand of a surgeon. 3. The injection device of claim 1 , wherein the housing is sealed so as to prevent ingress of fluids into the housing.

4. The injection device of claim 1 , wherein the drive mechanism comprises a screw-type mechanism having a member that can be linearly extended by an internal motor of the mechanism.

5. The injection device of claim 1 , wherein the central control unit comprises a microprocessor and associated memory.

6. The injection device of claim 1 , wherein the memory stores preset injection routines for controlling the drive mechanism that differ based upon the liquid substance that is being injected or the cannula that is being used. 7. The injection device of claim 1 , further comprising a wireless receiver contained within the housing that is configured to receive commands transmitted by a separate user control device.

8. The injection device of claim 1 , further comprising a battery contained within the housing that provides power to the drive mechanism and the central control unit.

9. The injection device of claim 8, further comprising an induction charging device contained in the housing that is used to recharge the battery. 0. A cartridge adapted for receipt within a handheld injection device, the cartridge comprising:

an elongated tube having a proximal end, a distal end, and an interior space; a plunger provided within the interior space adapted to travel along the tube toward the distal end of the tube; and

a cannula that extends from the distal end of the tube, the cannula having an elongated straight shaft and a curved distal end. 11 The cartridge of claim 10, wherein the tube is transparent.

12. The cartridge of claim 10, wherein the straight shaft ranges from approximately 20 gauge to 30 gauge.

13. The cartridge of claim 10, wherein the distal end has a radius of curvature that approximates the radius of curvature of a human retina.

14. The cartridge of claim 10, wherein the distal end is tapered.

15. The cartridge of claim 10, wherein the distal end has an elliptical cross- section.

16. The cartridge of claim 10, wherein the distal end defines a dissection tip that includes a beveled aperture that is defined by sharp angled edges that form a pointed, planar cutting blade.

17. The cartridge of claim 10, wherein the plunger comprises an aperture through which a substance can be delivered into the interior space of the tube.

18. The cartridge of claim 17, further comprising a screw that can be threaded into the aperture of the plunger to seal the interior space of the tube after delivery of the substance.

19. A method for delivering a substance to the retina, the method comprising:

passing a cannula of a handheld injection device through the sclera and into the vitreous;

positioning a dissection tip of the cannula adjacent the inner limiting membrane (ILM) of the retina;

piercing the ILM with the dissection tip of the cannula to form an opening in the ILM;

activating a drive mechanism contained within the handheld injection device to urge the substance through the cannula to deliver the substance to the retina.

20. The method of claim 19, wherein the substance comprises adeno- associated virus (AAV) vectors. 21. The method of claim 19, wherein the drive mechanism is activated by a microprocessor contained within the handheld injection device.

22. The method of claim 19, wherein the drive mechanism comprises a screw-type mechanism having a member that is linearly extended by an internal motor of the mechanism.

23. The method of claim 19, wherein the substance is delivered between the ILM and a nerve fiber layer of the retina.

24. The method of claim 19, wherein the substance is delivered underneath the retina.