Patent Description:
Macular degeneration is a medical condition that affects the macula, such that people suffering from macular degeneration may experience lost or degraded central vision while retaining some degree of peripheral vision. Macular degeneration may be caused by various factors such as age (also known as "AMD") and genetics. Macular degeneration may occur in a "dry" (nonexudative) form, where cellular debris known as drusen accumulates between the retina and the choroid, resulting in an area of geographic atrophy. Macular degeneration may also occur in a "wet" (exudative) form, where blood vessels grow up from the choroid behind the retina. Even though people having macular degeneration may retain some degree of peripheral vision, the loss of central vision may have a significant negative impact on the quality of life. Moreover, the quality of the remaining peripheral vision may be degraded and in some cases may disappear as well. It may therefore be desirable to provide treatment for macular degeneration in order to prevent or reverse the loss of vision caused by macular degeneration. In some cases it may be desirable to provide such treatment in a highly localized fashion, such as by delivering a therapeutic substance in the subretinal layer (under the neurosensory layer of the retina and above the retinal pigment epithelium) directly adjacent to the area of geographic atrophy, near the macula. However, since the macula is at the back of the eye and underneath the delicate layer of the retina, it may be difficult to access the macula in a practical fashion.

While a variety of surgical methods and instruments have been made and used to treat an eye, it is believed that no one prior to the inventors has made or used the invention described in the appended claims.

<CIT> discloses a sub-retinal tangential needle catheter guide and introducer including a body, a cannula and a needle slidably disposed in the cannula.

<CIT> discloses catheter devices which are useable to form extravascular passageways from a blood vessel to a vascular or non-vascular target location. In a particular embodiment, the device comprises a retractable outer catheter sheath and an elongate inner member with a pre-bent resilient tube formed within the distal portion thereof. The elongate inner member has a blunt distal tip and an elongate side opening formed therein such that when the outer catheter sheath is retracted in the proximal direction, the pre-bent resilient tubular member will spring outwardly to its pre-bent, laterally-curved configuration. A pre-bent, resilient tissue penetrating element can then advance out of a distal end of the inner tube member. <CIT> discloses devices for delivery of substances to extravascular treatment sites, including a vessel wall penetrating catheter, a penetrator which is advanced from the catheter so as to penetrate outwardly through the wall of the blood vessel, and a delivery catheter which is passed through a lumen of the penetrator to the target site.

The present invention provides an apparatus as recited in the claims. Aspects, embodiments, examples and methods of the present disclosure which are not claimed per se, are provided for illustrative purposes and are considered useful for giving context to the invention.

For clarity of disclosure, the terms "proximal" and "distal" are defined herein relative to a surgeon or other operator grasping a surgical instrument having a distal surgical end effector. The term "proximal" refers the position of an element closer to the surgeon or other operator and the term "distal" refers to the position of an element closer to the surgical end effector of the surgical instrument and further away from the surgeon or other operator.

<FIG> shows an exemplary instrument (<NUM>) that is configured for use in a procedure for the subretinal administration of a therapeutic agent to an eye of a patient from a suprachoroidal approach. Instrument (<NUM>) comprises a body (<NUM>) and a flexible cannula (<NUM>) extending distally from body (<NUM>). Cannula (<NUM>) of the present example has a generally rectangular cross section, though any other suitable cross-sectional profile (e.g., elliptical, etc.) may be used. Cannula (<NUM>) is generally configured to support a needle (<NUM>) that is slidable within cannula (<NUM>), as will be described in greater detail below.

In the present example, cannula (<NUM>) comprises a flexible material such as Polyether block amide (PEBA), which may be manufactured under the trade name PEBAX. Of course, any other suitable material or combination of materials may be used. Also in the present example, cannula (<NUM>) has a cross-sectional profile dimension of approximately <NUM> by <NUM>, with a length of approximately <NUM>. Altematively, any other suitable dimensions may be used. As will be described in greater detail below, cannula (<NUM>) is flexible enough to conform to specific structures and contours of the patient's eye, yet cannula (<NUM>) has sufficient column strength to permit advancement of cannula (<NUM>) between the sclera and choroid of patient's eye without buckling. By way of example only, cannula (<NUM>) may be configured and operable in accordance with at least some of the teachings of <CIT>.

As can be seen in <FIG> and <FIG>, cannula (<NUM>) comprises a body (<NUM>), a closed distal end (<NUM>), and a lateral opening (<NUM>) that is located proximal to distal end (<NUM>). In the present example, distal end (<NUM>) has a rounded configuration. It should be understood that distal end (<NUM>) may have any suitable kind of curvature. It should also be understood that distal end (<NUM>) may have any other sui table kind of configuration (e.g., beveled, etc.). In the present example, distal end (<NUM>) is configured to provide separation between the sclera and choroid layers to enable cannula (<NUM>) to be advanced between such layers while not inflicting trauma to the sclera or choroid layers. Also in the present example, the region of body (<NUM>) that defines lateral opening (<NUM>) is beveled, as best seen in <FIG>. Alternatively, the edge of lateral opening (S6) may have any other suitable configuration.

As best seen in <FIG>, a needle guide (<NUM>) is disposed within the hollow interior of cannula (<NUM>). By way of example only, needle guide (<NUM>) may be secured within cannula (<NUM>) by a press or interference fit, by adhesives, by mechanical locking mechanisms, and/or in any other suitable fashion. Needle guide (<NUM>) includes a curved distal end (<NUM>) that leads to lateral opening (<NUM>) of cannula (<NUM>), such that a lumen (<NUM>) of needle guide (<NUM>) distally terminates at lateral opening (<NUM>). The portion of needle guide (<NUM>) that is proximal to distal end (<NUM>) is substantially straight. Needle guide (<NUM>) may be formed of plastic, stainless steel, and/or any other suitable biocompatible material(s).

Needle (<NUM>) of the present example has a sharp distal tip (<NUM>) and defines a lumen (<NUM>). Distal tip (<NUM>) of the present example has a lancet configuration. In some other versions, distal tip (<NUM>) has a tri-bevel configuration or any other configuration as described in <CIT>. Still other suitable forms that distal tip (<NUM>) may take will be apparent to those of ordinary skill in the art in view of the teachings herein. Needle (<NUM>) of the present example comprises a stainless steel hypodermic needle that is sized to deliver the therapeutic agent while being small enough to minimize incidental trauma as needle (<NUM>) penetrates tissue structures of the patient's eye, as will be described in greater detail below. While stainless steel is used in the present example, it should be understood that any other suitable material(s) may be used, including but not limited to nitinol, etc..

By way of example only, needle (<NUM>) may be <NUM> gauge with a <NUM> inner diameter, although other suitable sizes may be used. For instance, the outer diameter of needle (<NUM>) may fall within the range of <NUM> gauge to <NUM> gauge: or more particularly within the range of <NUM> gauge to <NUM> gauge: or more particularly within the range of <NUM> gauge to <NUM> gauge. As another merely illustrative example, the inner diameter of needle (<NUM>) may fall within the range of approximately <NUM> to approximately <NUM>; or more particularly within the range of approximately <NUM> to approximately <NUM>; or more particularly within the range of approximately <NUM> to approximately <NUM>.

Needle (<NUM>) is slidably disposed within lumen (<NUM>) of needle guide (<NUM>). Needle guide (<NUM>) is generally configured to direct needle (<NUM>) upwardly along an exit axis (EA) that is obliquely oriented relative to the longitudinal axis (LA) of cannula (<NUM>) through lateral opening (<NUM>) of cannula (<NUM>). This is shown in the sequence depicted in <FIG>, in which <FIG> shows needle (<NUM>) in a proximal position (where distal tip (<NUM>) of needle (<NUM>) is fully contained in lumen (<NUM>) of needle guide (<NUM>)), and <FIG> shows needle (<NUM>) in a distal position (where distal tip (<NUM>) of needle (<NUM>) is outside of needle guide (<NUM>)). While needle (<NUM>) is flexible, needle (<NUM>) of the present example, which is not under the scope of the present invention, is resiliently biased to assume a straight configuration. Thus, as shown in <FIG>, the portion of needle (<NUM>) that extends outside of cannula (<NUM>) and needle guide (<NUM>) is substantially straight, extending along exit axis (EA). In particular, at least a substantial length of the portion of needle (<NUM>) that extends outside of cannula (<NUM>) and needle guide (<NUM>) is coaxially aligned with exit axis (EA).

It should be understood that the depiction of exit axis (EA) in <FIG> may be somewhat exaggerated, for illustrative purposes only. In some versions, curved distal end (<NUM>) is configured to direct needle (<NUM>) along an exit axis (EA) that extends distally from cannula (<NUM>) at an angle of approximately <NUM>° to approximately <NUM>° relative to the longitudinal axis (LA) of cannula (<NUM>). It should be understood that such an angle may be desirable to deflect needle (<NUM>) in a direction to ensure penetration of needle into the choroid and to minimize the possibility of needle (<NUM>) continuing beneath the choroid through the suprachoroidal space (as opposed to penetrating through the choroid) and the possibility of retinal perforation. By way of further example only, curved distal portion (<NUM>) may urge needle (<NUM>) to exit cannula (<NUM>) along an exit axis (EA) that is oriented at an angle within the range of approximately <NUM>° to approximately <NUM>° relative to the longitudinal axis (LA) of cannula (<NUM>); or more particularly within the range of approximately <NUM>° to approximately <NUM>° relative to the longitudinal axis (LA) of cannula (<NUM>); or more particularly within the range of approximately <NUM>° to approximately <NUM>° relative to the longitudinal axis (LA) of cannula (<NUM>).

As shown in <FIG>, instrument (<NUM>) of the present example further comprises an actuation knob (<NUM>) located at the proximal end of body (<NUM>). Actuation knob (<NUM>) is rotatable relative to body (<NUM>) to thereby selectively translate needle (<NUM>) longitudinally relative to cannula (<NUM>). In particular, actuation knob (<NUM>) is rotatable in a first angular direction to drive needle (<NUM>) distally relative to cannula (<NUM>); and in a second angular direction to drive needle (<NUM>) proximally relative to cannula (<NUM>). By way of example only, instrument (<NUM>) may provide such functionality through knob (<NUM>) in accordance with at least some of the teachings of <CIT>. Alternatively, any other suitable kind of actuation feature(s) may be used to drive needle (<NUM>) longitudinally relative to cannula (<NUM>).

In the present example, knob (<NUM>) is rotatable through a complete range of motion that corresponds to advancement of needle (<NUM>) to a position relative to cannula (<NUM>) to a predetermined amount of penetration within an eye of a patient. In other words, instrument (<NUM>) is configured such that an operator rotates knob (<NUM>) until knob (<NUM>) can no longer rotate, or until knob (<NUM>) begins to slip or "freewheel" in a clutch assembly, to properly position needle (<NUM>) within an eye of a patient. In some examples, the predetermined amount of advancement of needle (<NUM>) relative to cannula (<NUM>) is between approximately <NUM> to approximately <NUM>; or more particularly within the range of approximately <NUM> to approximately <NUM>; or more particularly within the range of approximately <NUM> to approximately <NUM>, or more particularly to approximately <NUM>.

In addition or in the alternative, instrument (<NUM>) may be equipped with certain tactile feedback features to indicate to an operator when needle (<NUM>) has been advanced to certain predetermined distances relative to cannula (<NUM>). Accordingly, an operator may determine the desired depth of penetration of needle (<NUM>) into a patient's eye based on direct visualization of indicia on instrument and/or based on tactile feedback from instrument (<NUM>). Of course, such tactile feedback features may be combined with the present example, as will be apparent to those of ordinary skill in the art in view of the teachings herein.

As also shown in <FIG>, a pair of supply tubes (<NUM>, <NUM>) extend proximally from actuator knob (<NUM>). In the present example, first supply tube (<NUM>) is configured to couple with a source of bleb fluid (<NUM>) (e.g., BSS); while second supply tube (<NUM>) is configured to couple with a source of therapeutic agent (<NUM>). It should be understood that each fluid supply tube (<NUM>, <NUM>) may include a conventional luer feature and/or other structures permitting fluid supply tubes (<NUM>, <NUM>) to be coupled with respective fluid sources. Fluid supply tubes (<NUM>, <NUM>) lead to a valve assembly that includes actuation arms (<NUM>). Actuation arms (<NUM>) are pivotable to selectively change the state of the valve assembly. Based on the pivotal position of actuation arms (<NUM>), the valve assembly is operable to selectively pinch or otherwise open/close the supply of fluid from fluid supply tubes (<NUM>, <NUM>) to lumen (<NUM>) of needle (<NUM>). Thus, actuation arms (<NUM>) are operable to selectively control the delivery of bleb fluid (<NUM>) and therapeutic agent (<NUM>) via needle (<NUM>). By way of example only, the valve assembly may be configured and operable in accordance with at least some of the teachings of <CIT>. Other suitable features and configurations that may be used to control fluid delivery via needle (<NUM>) will be apparent to those of ordinary skill in the art in view of the teachings herein.

It should be understood that the features and operability of instrument (<NUM>) may be varied in numerous ways. By way of example only, needle (<NUM>) may be replaced with needle (<NUM>) as described in greater detail below. In addition, cannula (<NUM>) may be replaced with cannula (<NUM>) as will be described in greater detail below. In addition, instrument (<NUM>) may be modified in accordance with at least some of the teachings of <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and/or <CIT>. Other suitable modifications will be apparent to those of ordinary skill in the art in view of the teachings herein.

<FIG> show an exemplary procedure for subretinal delivery of therapeutic agent from a suprachoroidal approach using instrument (<NUM>) described above. By way of example only, the method described herein may be employed to treat macular degeneration and/or other ocular conditions. Although the procedure described herein is discussed in the context of the treatment of age-related macular degeneration, it should be understood that no such limitation is intended or implied. For instance, in some merely exemplary alternative procedures, the same techniques described herein may be used to treat retinitis pigmentosa, diabetic retinopathy, and/or other ocular conditions. Additionally, it should be understood that the procedure described herein may be used to treat either dry or wet age-related macular degeneration.

In the present example, the procedure begins by an operator immobilizing tissue surrounding a patient's eye (<NUM>) (e.g., the eyelids) using a speculum, and/or any other instrument suitable for immobilization. While immobilization described herein with reference to tissue surrounding eye (<NUM>), it should be understood that eye (<NUM>) itself may remain free to move. Once the tissue surrounding eye (<NUM>) has been immobilized, an eye chandelier port (<NUM>) is inserted into eye (<NUM>), as shown in <FIG>, to provide intraocular illumination when the interior of eye (<NUM>) is viewed through the pupil. In the present example, eye chandelier port (<NUM>) is positioned in the inferior medial quadrant such that a superior temporal quadrant sclerotomy may be preformed. Eye chandelier port (<NUM>) is positioned to direct light onto the interior of eye (<NUM>) to illuminate at least a portion of the retina (e.g., including at least a portion of the macula). As will be understood, such illumination corresponds to an area of eye (<NUM>) that is being targeted for delivery of therapeutic agent.

In the present example, only chandelier port (<NUM>) is inserted at the stage shown in <FIG>, without yet inserting an optical fiber (<NUM>) into port (<NUM>). in some other versions, an optical fiber (<NUM>) may be inserted into chandelier port (<NUM>) at this stage. In either case, a microscope may optionally be utilized to visually inspect the eye to confirm proper positioning of eye chandelier port (<NUM>) relative to the target site. Although <FIG> shows a particular positioning of eye chandelier port (<NUM>), it should be understood that eye chandelier port (<NUM>) may have any other positioning as will be apparent to those of ordinary skill in the art in view of the teachings herein.

Once eye chandelier port (<NUM>) has been positioned, the sclera (<NUM>) may be accessed by dissecting the conjunctiva by incising a flap in the conjunctiva and pulling the flap posteriorly. After such a dissection is completed, the exposed surface (<NUM>) of the sclera (<NUM>) may optionally be blanched using a cautery tool to minimize bleeding. Once conjunctiva dissection is complete, the exposed surface (<NUM>) of the sclera (<NUM>) may optionally be dried using a WECK-CEL or other suitable absorbent device. A template may then be used to mark eye (<NUM>), as described in <CIT>. An operator may then use a visual guide created using the template to attach a suture loop assembly (<NUM>) and to perform a sclerotomy, as shown in <FIG>, using a conventional scalpel (<NUM>) or other suitable cutting instrument. The sclerotomy procedure forms a small incision through sclera (<NUM>) of eye (<NUM>). The sclerotomy is preformed with particular care to avoid penetration of the choroid (<NUM>). Thus, the sclerotomy procedure provides access to the space between sclera (<NUM>) and choroid (<NUM>). Once the incision is made in eye (<NUM>), a blunt dissection may optionally be performed to locally separate sclera (<NUM>) from choroid (<NUM>). Such a dissection may be performed using a small blunt elongate instrument, as will be apparent to those of ordinary skill in the art in view of the teachings herein.

With the sclerotomy procedure performed, an operator may insert cannula (<NUM>) of instrument (<NUM>) through incision (<NUM>) and into the space between sclera (<NUM>) and choroid (<NUM>). As can be seen in <FIG>, cannula (<NUM>) is directed through suture loop assembly (<NUM>) and into the incision. Suture loop assembly (<NUM>) may stabilize cannula (<NUM>) during insertion. Additionally, suture loop assembly (<NUM>) maintains cannula (<NUM>) in a generally tangential orientation relative to the incision. Such tangential orientation may reduce trauma as cannula (<NUM>) is guided through the incision. As cannula (<NUM>) is inserted into the incision through suture loop assembly (<NUM>), an operator may use forceps or other instruments to further guide cannula (<NUM>) along an atraumatic path. Of course, use of forceps or other instruments is merely optional, and may be omitted in some examples.

Although not shown, it should be understood that in some examples cannula (<NUM>) may include one or more markers on the surface of cannula (<NUM>) to indicate various depths of insertion. While merely optional, such markers may be desirable to aid an operator in identifying the proper depth of insertion as cannula (<NUM>) is guided along an atraumatic path. For instance, the operator may visually observe the position of such markers in relation to suture loop assembly (<NUM>) and/or in relation to the incision in the sclera (<NUM>) as an indication of the depth to which cannula (<NUM>) is inserted in eye (<NUM>). By way of example only, one such marker may correspond to an approximately <NUM> depth of insertion of cannula (<NUM>).

As shown in <FIG>, once cannula (<NUM>) is at least partially inserted into eye (<NUM>), an operator may insert an optical fiber (<NUM>) into eye chandelier port (<NUM>) if the fiber (<NUM>) had not yet been inserted at this stage. With eye chandelier port (<NUM>) in place and assembled with optical fiber (<NUM>), an operator may activate eye chandelier port (<NUM>) by directing light through optical fiber (<NUM>) to provide illumination of eye (<NUM>) and thereby visualize the interior of eye (<NUM>). Further adjustments to the positioning of cannula (<NUM>) may optionally be made at this point to ensure proper positioning relative to the area of geographic atrophy of retina (<NUM>). In some instances, the operator may wish to rotate the eye (<NUM>), such as by pulling on suture loop assembly (<NUM>), to direct the pupil of the eye (<NUM>) toward the operator in order to optimize visualization of the interior of the eye (<NUM>) via the pupil.

<FIG> show cannula (<NUM>) as it is guided between sclera (<NUM>) and choroid (<NUM>) to the delivery site for the therapeutic agent. In the present example, the delivery site corresponds to a generally posterior region of eye (<NUM>) adjacent to an area of geographic atrophy of retina (<NUM>). In particular, the delivery site of the present example is superior to the macula, in the potential space between the neurosensory retina and the retinal pigment epithelium layer. By way of example only, the operator may rely on direct visualization through a microscope directed through the pupil of eye (<NUM>) as cannula (<NUM>) is being advanced through the range of motion shown in <FIG>, with illumination provided through fiber (<NUM>) and port (<NUM>). Cannula (<NUM>) may be at least partially visible through a retina (<NUM>) and choroid (<NUM>) of eye (<NUM>). Visual tracking may be enhanced in versions where an optical fiber is used to emit visible light through the distal end of cannula (<NUM>).

Once cannula (<NUM>) has been advanced to the delivery site as shown in <FIG>, an operator may advance needle (<NUM>) of instrument (<NUM>) as described above by actuating knob (<NUM>). As can be seen in <FIG> and <FIG>, needle (<NUM>) is advanced relative to cannula (<NUM>) such that needle (<NUM>) pierces through choroid (<NUM>) without penetrating retina (<NUM>). Immediately prior to penetrating choroid (<NUM>), needle (<NUM>) may appear under direct visualization as "tenting" the surface of choroid (<NUM>). In other words, needle (<NUM>) may deform choroid (<NUM>) by pushing upwardly on choroid (<NUM>), providing an appearance similar to a tent pole deforming the roof of a tent. Such a visual phenomenon may be used by an operator to identify whether choroid (<NUM>) is about to be pierced and the location of any eventual piercing. The particular amount of needle (<NUM>) advancement sufficient to initiate "tenting" and subsequent piercing of choroid (<NUM>) may be of any suitable amount as may be determined by a number of factors such as, but not limited to, general patient anatomy, local patient anatomy, operator preference, and/or other factors. As described above, a merely exemplary range of needle (<NUM>) advancement may be between approximately <NUM> and approximately <NUM>; or more particularly between approximately <NUM> and approximately <NUM>.

In the present example, after the operator has confirmed that needle (<NUM>) has been properly advanced by visualizing the tenting effect described above, the operator infuses a balanced salt solution (BSS) or other similar solution as needle (<NUM>) is advanced relative to cannula (<NUM>). Such a BSS may form a leading bleb (<NUM>) ahead of needle (<NUM>) as needle (<NUM>) is advanced through choroid (<NUM>). Leading bleb (<NUM>) may be desirable for two reasons. First, as shown in <FIG> and <FIG>, leading bleb (<NUM>) may provide a further visual indicator to an operator to indicate when needle (<NUM>) is properly positioned at the delivery site. Second, leading bleb (<NUM>) may provide a barrier between needle (<NUM>) and retina (<NUM>) once needle (<NUM>) has penetrated choroid (<NUM>). Such a barrier may push the retinal wall outwardly, thereby minimizing the risk of retinal perforation as needle (<NUM>) is advanced to the delivery site. In some versions, a foot pedal is actuated in order to drive leading bleb (<NUM>) out from needle (<NUM>). Alternatively, other suitable features that may be used to drive leading bleb (<NUM>) out from needle (<NUM>) will be apparent to those of ordinary skill in the art in view of the teachings herein.

Once the operator visualizes leading bleb (<NUM>), the operator may cease infusion of BSS, leaving a pocket of fluid as can be seen in <FIG> and <FIG>. Next, a therapeutic agent (<NUM>) may be infused by actuating a syringe or other fluid delivery device as described in various references cited herein. The particular therapeutic agent (<NUM>) delivered may be any suitable therapeutic agent configured to treat an ocular condition. Some merely exemplary suitable therapeutic agents may include, but are not necessarily limited to, drugs having smaller or large molecules, therapeutic cell solutions, certain gene therapy solutions, tissue plasminogen activators, and/or any other suitable therapeutic agent as will be apparent to those of ordinary skill in the art in view of the teachings herein. By way of example only, the therapeutic agent (<NUM>) may be provided in accordance with at least some of the teachings of <CIT>. In addition to, or as an alternative to, being used to deliver a therapeutic agent (<NUM>), instrument (<NUM>) and variations thereof may be used to provide drainage and/or perform other operations.

In the present example, the amount of therapeutic agent (<NUM>) that is ultimately delivered to the delivery site is approximately 50uL, although any other suitable amount may be delivered. In some versions, a foot pedal is actuated in order to drive agent <NUM>) out from needle (<NUM>). Alternatively, other suitable features that may be used to drive agent (<NUM>) out from needle (<NUM>) will be apparent to those of ordinary skill in the art in view of the teachings herein. Delivery of therapeutic agent (<NUM>) may be visualized by an expansion of the pocket of fluid as can be seen in <FIG> and <FIG>. As shown, therapeutic agent (<NUM>) essentially mixes with the fluid of leading bleb (<NUM>) as therapeutic agent (<NUM>) is injected into the surprachoroidal, subretinal space.

Once delivery is complete, needle (<NUM>) may be retracted by rotating knob (<NUM>) in a direction opposite to that used to advance needle (<NUM>); and cannula (<NUM>) may then be withdrawn from eye (<NUM>). It should be understood that because of the size of needle (<NUM>), the site where needle (<NUM>) penetrated through choroid (<NUM>) is self sealing, such that no further steps need be taken to seal the delivery site through choroid (<NUM>). Suture loop assembly (<NUM>) and chandelier (<NUM>) may be removed, and the incision in the sclera (<NUM>) may be closed using any suitable conventional techniques.

As noted above, the foregoing procedure may be carried out to treat a patient having macular degeneration. In some such instances, the therapeutic agent (<NUM>) that is delivered by needle (<NUM>) may comprise cells that are derived from postpartum umbilicus and placenta. As noted above, and by way of example only, the therapeutic agent (<NUM>) may be provided in accordance with at least some of the teachings of <CIT>. Alternatively, needle (<NUM>) may be used to deliver any other suitable substance or substances, in addition to or in lieu of those described in <CIT> and/or elsewhere herein. By way of example only, therapeutic agent (<NUM>) may comprise various kinds of drugs including but not limited to small molecules, large molecules, cells, and/or gene therapies. It should also be understood that macular degeneration is just one merely illustrative example of a condition that may be treated through the procedure described herein. Other biological conditions that may be addressed using the instruments and procedures described herein will be apparent to those of ordinary skill in the art.

It should also be understood that the procedure described above may be carried out in accordance with any of the teachings of <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; <CIT>; and/or <CIT>.

Several variables may affect the relationship between the exit angle (EA) of needle (<NUM>) and the choroid (<NUM>) of any given patient. It should be understood that the choroid (<NUM>) and the retina (<NUM>) are very thin and have relatively little structural integrity. Thus, even when a very flexible cannula (<NUM>) is used, cannula (<NUM>) may tend to provide substantial separation between the choroid (<NUM>) and the sclera (<NUM>) as cannula (<NUM>) is inserted between the choroid (<NUM>) and the sclera (<NUM>). The degree of separation may vary from patient to patient (e.g., based on normal anatomical variation and/or based on the patient's disease state, etc.). In cases where the separation is truly substantial, the exit angle (EA) of needle (<NUM>) may be insufficient to result in distal tip (<NUM>) passing fully through the choroid (<NUM>). In other words, needle (<NUM>) may continue through the suprachoroidal space without fully penetrating the choroid (<NUM>).

<FIG> shows an exemplary scenario where cannula (<NUM>) has elevated the choroid (<NUM>) and retina (<NUM>) away from the sclera (<NUM>) to the point where a substantial gap (<NUM>) is defined between the sclera (<NUM>) and the choroid (<NUM>). As also shown in <FIG>, the exit angle (EA) is oriented such that needle (<NUM>) would not penetrate the choroid (<NUM>); and further such that needle (<NUM>) would eventually engage the sclera (<NUM>-<NUM>). <FIG> shows needle (<NUM>) advanced distally along this exit angle (EA). As shown, needle (<NUM>) passes tangentially along the choroid (<NUM>) without ever breaching the choroid (<NUM>). In some other instances, needle (<NUM>) may pass partially through the choroid (<NUM>) and immediately exit the choroid (<NUM>) without ever reaching the subretinal space between the choroid (<NUM>) and the retina (<NUM>).

If the operator determines (e.g., based on the absence of a choroidal "tenting" observation as described above) that needle (<NUM>) has not fully penetrated the choroid (<NUM>) despite needle (<NUM>) being advanced fully distally, the operator may retract needle (<NUM>) proximally, slightly reposition cannula (<NUM>) and/or another portion of instrument (<NUM>) in order to provide a better orientation for the exit angle (EA), and then try advancing needle (<NUM>) distally again. Even with such efforts, it may still be very difficult or even impossible in some cases to successfully penetrate the choroid (<NUM>) with needle (<NUM>). Even in cases where efforts to reposition are successful, the success rate may be highly dependent on the skill of the operator, and the repositioning efforts will add time to the procedure. Moreover, the repositioning may increase the risk of tissue trauma, increase the risk of bleb collapse, and/or increase the risk of cell egress into the suprachoroidal space.

It may seem apparent to address the above-noted issues by simply modifying needle guide (<NUM>) to provide a steeper exit angle (EA). However, this kind of modification may be unsuitable for many patients. In particular, increasing the exit angle (EA) by providing a more pronounced bend in distal end (<NUM>) of needle guide (<NUM>) may increase the risk of needle (<NUM>) perforating the retina (<NUM>) in some patients, particularly in those where the gap (<NUM>) created by cannula (<NUM>) between the sclera (<NUM>) and the choroid (<NUM>) is less pronounced than the gap (<NUM>) shown in <FIG>; including cases where the gap (<NUM>) is non-existent. It may therefore be desirable to provide a more nuanced solution that provides greater consistency in penetration of the choroid (<NUM>) without substantially increasing the risk of penetration of the retina (<NUM>). Such a solution may provide better accommodation of anatomical variations across patients; accommodate variation in operator technique and expertise; and minimize the level of operator training required.

<FIG> shows an exemplary alternative needle (<NUM>) that may be incorporated into instrument (<NUM>) in place of needle (<NUM>). In some instances, needle (<NUM>) may be substituted for needle (<NUM>) without modifying any other aspects of instrument (<NUM>). Needle (<NUM>) of the present example has a distal tip (<NUM>) that is configured and operable just like distal tip (<NUM>) described above. As shown in <FIG>, needle (<NUM>) also defines a lumen (<NUM>) that is configured and operable just like lumen (<NUM>) described above. Unlike needle (<NUM>), however, needle (<NUM>) of the present example includes a substantially straight proximal portion (<NUM>), a substantially straight distal portion (<NUM>), and a bent portion (<NUM>) located between proximal and distal portions (<NUM>, <NUM>). In the present example, needle (<NUM>) is formed of nitinol, though it should be understood that any other suitable material(s) (e.g., stainless steel, etc.) may be used.

Needle (<NUM>) is configured to provide bent portion (<NUM>) as a preformed feature, such that needle (<NUM>) is resiliently biased to assume the configuration shown in <FIG>. By way of example only, bent portion (<NUM>) may be configured to have a constant radius of curvature between approximately <NUM> and approximately <NUM>; a constant radius of curvature between approximately <NUM> and approximately <NUM>; a constant radius of curvature between approximately <NUM> and approximately <NUM>; or a constant radius of curvature between approximately <NUM> and approximately <NUM>. In some versions, bent portion (<NUM>) has a radius of curvature of approximately <NUM>. In some other versions, bent portion (<NUM>) has a radius of curvature of approximately <NUM>. In some other versions, bent portion (<NUM>) has a radius of curvature of approximately <NUM>. It should be understood that the radius of curvature must be carefully selected because if the radius is too small, there may be an increased risk of perforating the retina (<NUM>); and if the radius is too large, the needle (<NUM>) may still fail to fully penetrate the choroid (<NUM>).

While the radius of curvature of bent portion (<NUM>) is constant in the present example, in some other versions the radius of curvature may be variable. For instance, some variations of needle (<NUM>) may provide a larger radius of curvature in a region of needle (<NUM>) that remains disposed in cannula (<NUM>), even when needle (<NUM>) is in a distally extended position; with a smaller radius of curvature in a region of needle (<NUM>) that extends distally from cannula (<NUM>) when needle (<NUM>) is in a distally extended position. This kind of configuration may impart a slight precurvature to cannula (<NUM>), which may further assist in cannula (<NUM>) conforming to the curved inner wall of sclera (<NUM>), which may in turn reduce the occurrence (or magnitude) of gap (<NUM>).

As shown in <FIG>, needle (<NUM>) is slidably disposed in needle guide (<NUM>) within cannula (<NUM>). While <FIG> shows needle (<NUM>) in a partially advanced state, it should be understood that needle (<NUM>) may be retracted further proximally in needle guide (<NUM>) such that distal tip (<NUM>) does not protrude through lateral opening (<NUM>). As shown in <FIG>, as needle (<NUM>) begins to exit cannula (<NUM>) via lateral opening (<NUM>), the distally protruding portion of needle (<NUM>) is oriented along a first exit axis (EA<NUM>). At this stage, bent portion (<NUM>) and part of distal portion (<NUM>) are still contained within needle guide (<NUM>), such that needle guide (<NUM>) prevents needle (<NUM>) from reaching the configuration shown in <FIG>.

As the operator continues to advance needle (<NUM>) distally relative to cannula (<NUM>), more of needle (<NUM>) protrudes distally from lateral opening (<NUM>), as shown in <FIG>. Due to the resilient bias of needle (<NUM>), the now longer protruding portion of needle (<NUM>) is oriented along a second exit axis (EA<NUM>). Second exit axis (EA<NUM>) defines an angle with the longitudinal axis (LA) that is larger than the angle defined between first exit axis (EA<NUM>) and the longitudinal axis (LA). As the operator continues to advance needle (<NUM>) further distally relative to cannula (<NUM>), even more of needle (<NUM>) protrudes distally from lateral opening (<NUM>), as shown in <FIG>. Due to the resilient bias of needle (<NUM>), the now longer protruding portion of needle (<NUM>) is oriented along a third exit axis (EA<NUM>). Third exit axis (EA<NUM>) defines an angle with the longitudinal axis (LA) that is larger than the angle defined between second exit axis (EA<NUM>) and the longitudinal axis (LA). Thus, the further needle (<NUM>) is advanced, the larger the angle defined between the exit axis (EA) and the longitudinal axis (LA). It should be understood that the depictions of exit axes (EA<NUM>, EA<NUM>, EA<NUM>) in <FIG> may be somewhat exaggerated, for illustrative purposes only.

As shown in <FIG>, needle (<NUM>) may be particularly useful in cases where cannula creates a substantial gap (<NUM>) between the sclera (<NUM>) and the choroid (<NUM>). It should be understood that the gap (<NUM>) in <FIG> is substantially the same as the gap (<NUM>) in <FIG>. As noted above, due to the gap (<NUM>) in <FIG> and the associated relationships between the anatomical structures and the instrument (<NUM>) structures, needle (<NUM>) is unable to penetrate choroid (<NUM>). However, as shown in <FIG>, the curvature of needle (<NUM>) allows needle (<NUM>) to penetrate choroid (<NUM>) despite the presence of gap (<NUM>) and the associated relationships between the anatomical structures and the instrument (<NUM>) structures.

As noted above, the exit angle (EA) of needle (<NUM>) varies based on the extent to which needle (<NUM>) is extended from cannula (<NUM>). It should be understood that this variation in the exit angle (EA) will allow the operator to control the optimal exit angle (EA) by controlling the amount of needle (<NUM>) extension. This may allow for shallower angles (less extension) for some patients and steeper angles (more extension) for other patients, to more consistently be able to achieve penetration of the choroid (<NUM>) in a relatively safe and efficient manner, eliminating the need for other mitigations or workarounds that would otherwise be required from the scenario depicted in <FIG>.

As noted above, cannula (<NUM>) includes a closed distal end (<NUM>) and a lateral opening (<NUM>) that is located proximal to distal end (<NUM>). In some instances, it may be desirable to provide an alternative cannula that has an open distal end, without a lateral opening. By way of example only, this may provide simplified manufacturing processes. Since it may still be desirable to have a needle exit the cannula at such that the distal tip of the needle is oriented along an axis that is oblique to the longitudinal axis of the cannula, it may be desirable to use a needle with a preformed curve in versions where the cannula has an open distal end.

<FIG> shows an exemplary alternative cannula (<NUM>) that may be readily incorporated into instrument (<NUM>) in place of cannula (<NUM>). Cannula (<NUM>) of this example has a flexible body (<NUM>) and a distal opening (<NUM>). Distal opening (<NUM>) is coaxially positioned on the longitudinal axis of cannula (<NUM>) in this example. In some other versions, distal opening (<NUM>) is offset from the longitudinal axis of cannula (<NUM>). By way of example only, cannula (<NUM>) may be formed of Polyether block amide (PEBA) and/or any other suitable kind(s) of material(s). Like cannula (<NUM>), cannula (<NUM>) of the present example has sufficient column strength to be advanced distally between the sclera (<NUM>) and choroid (<NUM>) of patient's eye without buckling.

An insert (<NUM>) is positioned within cannula (<NUM>). Insert (<NUM>) may be secured within cannula (<NUM>) by a press or interference fit, by adhesives, by mechanical locking mechanisms, and/or in any other suitable fashion. In the present example, insert (<NUM>) is formed of a polyimide material, though it should be understood that any other suitable biocompatible material(s) may be used. Insert (<NUM>) of the present example is substantially straight yet may bend with cannula (<NUM>). Needle (<NUM>) is slidably disposed in a lumen (<NUM>) defined by insert (<NUM>). When needle (<NUM>) is in a proximal position as shown in <FIG>, distal tip (<NUM>) of needle (<NUM>) is fully contained within lumen (<NUM>). At this stage, insert (<NUM>) constrains needle (<NUM>) such that needle (<NUM>) is held under stress in a substantially straight configuration. When needle (<NUM>) is in a distal position as shown in <FIG>, distal tip (<NUM>) of needle is positioned distally of cannula (<NUM>). At this stage, curved portion (<NUM>) is exposed such that the distal portion (<NUM>) of needle (<NUM>) is oriented along an exit axis that is oblique io the longitudinal axis of cannula (<NUM>). It should be understood that this configuration and orientation may position distal tip (<NUM>) at the subretinal space (i.e., between the choroid (<NUM>) and the retina <NUM>)).

It should be understood that any of the versions of the instruments described herein may include various other features in addition to or in lieu of those described above. By way of example only, any of the devices herein may also include one or more of the various features disclosed in any of the various references mentioned herein.

Versions described above may be designed to be disposed of after a single use, or they can be designed to be used multiple times. Upon cleaning and/or replacement of particular parts, some versions of the device may be reassembled for subsequent use either at a reconditioning facility, or by an operator immediately prior to a procedure.

Claim 1:
An apparatus (<NUM>) for subretinal administration of a therapeutic agent, the apparatus comprising:
(a) a body (<NUM>);
(b) a cannula (<NUM>) extending distally from the body (<NUM>), wherein the cannula (<NUM>) is flexible, wherein the cannula includes a distal end (<NUM>) that is configured to provide separation between sclera and choroid layers of a patient's eye to enable the cannula (<NUM>) to be advanced between the sclera and the choroid layers without inflicting trauma to the sclera or choroid layers; and
(c) a needle (<NUM>) slidably disposed in the cannula (<NUM>), wherein the needle (<NUM>) includes:
(i) a sharp distal tip (<NUM>), wherein the needle (<NUM>) is configured to translate relative to the cannula (<NUM>) between a proximal position and a distal position, wherein the distal tip (<NUM>) is configured to be positioned inside the cannula (<NUM>) when the needle (<NUM>) is in the proximal position, wherein the distal tip (<NUM>) is configured to be positioned outside the cannula (<NUM>) when the needle (<NUM>) is in the distal position;
(ii) a curved portion (<NUM>), wherein the needle (<NUM>) is resiliently biased to extend along a curve through the curved portion (<NUM>);
(iii) a straight proximal portion (<NUM>); and
(iv) a straight distal portion (<NUM>), wherein the curved portion (<NUM>) is longitudinally positioned between the straight proximal portion (<NUM>) and the straight distal portion (<NUM>).