Abstract:
A retinal treatment system for delivering therapeutic agents to a target location with a retina is disclosed herein. The retinal treatment system includes a console having a control system and a handheld device coupled to the control system. The handheld device includes an inner tube disposed within an outer tube and being axially moveable within the outer tube. The inner tube has a perforating tip that is configured to perforate an inner limiting membrane of the retina. The handheld device further includes a chamber coupled to a proximal end of the inner tube that is configured to receive a fluid containing therapeutic agents injectable from the perforating tip. The control system of the retinal treatment system permits a user to maintain a position of the handheld device relative to the retina and activate an injection of a portion of the fluid through the inner tube into the retina.

Description:
BACKGROUND 
       [0001]    The present disclosure relates to systems and methods for use during surgical procedures, and more particularly, to the delivery of therapeutic agents into subretinal space during an ophthalmic surgical procedure. 
         [0002]    Medical researchers are pioneering various treatments for diseases and conditions. Some conditions are pathogenic while others are congenital. The advancing knowledge of genetic therapies is providing hope for those suffering from a wide range of such conditions, including ophthalmic conditions. In seeking to treat certain eye problems, genes or stem cells may be injected through a fine needle inserted through the eye cavity and under the retina. A small perforation is made in the retina to access the subretinal space. A surgeon maintains the needle in place while another surgeon or assistant injects a fluid containing therapeutic agents through the needle. 
         [0003]    Thus, some operations currently require two surgeons to control the puncturing and the injection of fluid containing therapeutic agents. Positioning the needle in the retina depends entirely on the surgeon&#39;s observation and experience. Additionally, reflux of fluid back into the eye cavity through the puncture site makes it difficult to apply a consistent, desired volume of the therapeutic agent. 
         [0004]    Therefore, there remains a need for improved systems and methods for subretinal delivery of therapeutic agents. The present disclosure is directed to addressing one or more of the deficiencies in the prior art. 
       SUMMARY 
       [0005]    In one exemplary aspect, the present disclosure is directed to a retinal treatment device for delivering therapeutic agents to a target location within a retina. The retinal treatment device includes an outer tube having a lumen and having a distal end and a proximal end, the outer tube being sized to penetrate an eye to conduct retinal surgeries. The retinal treatment device further includes a flexible tip affixed to the distal end of the outer tube. The flexible tip is configured to flexibly conform to a retinal surface when abutted against the retinal surface. The retinal treatment device also includes an inner tube disposed within the lumen of the outer tube, the inner tube having a proximal end and a distal end. The distal end of the inner tube extends into the flexible tip, the inner tube configured to extend from the flexible tip and penetrate an inner limiting membrane of the retina. A chamber is coupled to the proximal end of the inner tube. The chamber is configured to receive a fluid containing therapeutic agents injectable through the inner tube beyond the inner limiting membrane of the retina when the inner tube penetrates the inner limiting membrane of the retina. 
         [0006]    In another exemplary aspect, the present disclosure is directed to a retinal treatment system for delivering therapeutic agents to a target location with a retina. The retinal treatment system includes a console having a control system and a handheld device coupled to the control system by a communication line. The handheld device includes an inner tube disposed within an outer tube and being axially moveable within the outer tube. The inner tube has a perforating tip at a distal end thereof that is configured to perforate an inner limiting membrane of the retina. The handheld device further includes a chamber coupled to a proximal end of the inner tube. The chamber is configured to receive a fluid containing therapeutic agents injectable from the perforating tip. The control system of the retinal treatment system permits a user to maintain a position of the handheld device relative to the retina and activate an injection of a portion of the fluid through the inner tube into the retina. 
         [0007]    In yet another exemplary aspect, the present disclosure is directed to a method of delivering therapeutic agents into a retina of an eye a patient. The method includes steps of penetrating a vitreous chamber of the eye with a retinal treatment device and of positioning the retinal treatment device in contact with the retina so as to form a seal by sealing means between the retinal treatment device and the retina. The method further includes a step of activating an injection routine that forms a bleb containing therapeutic agents in the retina and a step of withdrawing the retinal treatment device from the vitreous chamber. 
         [0008]    It is to be understood that both the foregoing general description and the following drawings and detailed description are exemplary and explanatory in nature and are intended to provide an understanding of the present disclosure without limiting the scope of the present disclosure. In that regard, additional aspects, features, and advantages of the present disclosure will be apparent to one skilled in the art from the following. 
     
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
         [0009]    The accompanying drawings illustrate embodiments of the devices and methods disclosed herein and together with the description, serve to explain the principles of the present disclosure. 
           [0010]      FIG. 1  is a cross-sectional illustration of an eye of a patient. 
           [0011]      FIG. 2  is a cross-sectional illustration of a portion of the retina of the eye shown in  FIG. 1 . 
           [0012]      FIG. 3  is an illustration of a retinal treatment system according to exemplary aspects of the present disclosure. 
           [0013]      FIG. 4  is a cross-sectional illustration of a subretinal delivery device according to exemplary aspects of the present disclosure. 
           [0014]      FIGS. 5A ,  5 B,  5 C,  5 D,  5 E, and  5 F are cross-sectional illustrations of distal ends of subretinal delivery devices according to exemplary aspects of the present disclosure. 
           [0015]      FIGS. 6A and 6B  are lateral views of alternative embodiments of a subretinal delivery device providing a seal at a retinal surface according to exemplary aspects of the present disclosure. 
           [0016]      FIGS. 7A ,  7 B, and  7 C are cross-sectional illustrations of subretinal delivery devices showing pressure-moderation mechanisms according to exemplary aspects of the present disclosure. 
           [0017]      FIGS. 8A and 8B  are cross-sectional illustrations of a subretinal delivery device with a delivery needle in two states according to exemplary aspects of the present disclosure. 
           [0018]      FIG. 9  is a flowchart of a method of delivering therapeutic agents into a retina of an eye of a patient according to exemplary aspects of the present disclosure. 
       
    
    
       [0019]    These figures are better understood by reference to the following detailed description. 
       DETAILED DESCRIPTION 
       [0020]    For the purposes of promoting an understanding of the principles of the present disclosure, reference will now be made to the embodiments illustrated in the drawings and specific language will be used to describe them. It will nevertheless be understood that no limitation of the scope of the present disclosure is intended. Any alterations and further modifications to the described devices, instruments, methods, and any further application of the principles of the present disclosure are fully contemplated as would normally occur to one skilled in the art to which the present disclosure relates. In particular, it is fully contemplated that the features, components, and/or steps described with respect to one embodiment may be combined with the features, components, and/or steps described with respect to other embodiments of the present disclosure. For simplicity, in some instances the same reference numbers are used throughout the drawings to refer to the same or like parts. 
         [0021]    The present disclosure relates generally to systems, delivery devices, and methods of delivering therapeutic agents into the subretinal area of a patient&#39;s eye. In some aspects, a delivery device ensures a roughly fixed depth of penetration by a needle into the subretinal space and provides a seal at the puncture site to prevent reflux of the fluid containing therapeutic agents, such as genes or stem cells, back into the eye cavity. In some aspects, the system permits the activation of an injection routine by a surgeon, while the surgeon maintains a tip of the delivery device within the retina of a patient. Thus, using the delivery device, a single surgeon may apply a treatment to a patient in a more controlled manner. 
         [0022]      FIG. 1  is a cross-sectional illustration of an eye  100 . A number of features of the eye  100  are illustrated herein. The eye  100  includes a sclera  102  that is coupled to a retinal membrane or retina  104  by a choroid (not illustrated in  FIG. 1 ). The choroid includes connective tissue to attach the retina  104  to the inside wall of the sclera  102  at the back of the eye  100  and to provide oxygen and nourishment to the outer layers of the retina  104 . A cornea  108  permits light to enter the eye  100 , the light being focused by a lens  110  through a vitreous chamber  112  onto the retina  104 , which contains photo-activated cells that transmit signals over the optic nerve  106  to the brain. 
         [0023]    Problems may develop in the eye that prevent the proper development and/or function of the retina as it provides signals to the brain for processing into cognizable images. A potential treatment or therapy for such eye problems including delivering genetic material and/or stem cells into a desired region of the subretinal space, the area between the outermost surface of the retina and the retinal pigment epithelium (RPE), just above the choroid, where the immune response may be sufficiently subdued. 
         [0024]    An area of interest  114  is shown in  FIG. 1  on a lower portion of the eye  100 . The area of interest  114  is shown in more detail in  FIG. 2 . 
         [0025]    Referring now to  FIG. 2 , the area of interest  114  of the eye  100  is shown in close-up to provide greater, schematic detail of the layers of the retina  104 . The layers are not drawn to scale. As shown in  FIG. 2 , the retina  104  includes several layers, including a main retinal layer  202 , a sub-retinal space  204 , and an opaque layer  206 . The retinal layer  202  includes an inner limiting membrane that is in contact with the vitreous humor that fills the vitreous chamber  112 . The retinal layer  202  further includes a nerve fiber sub-layer, a ganglion cell sub-layer, an inner plexiform sub-layer, an inner nuclear sub-layer, an outer plexiform sub-layer, and an outer nuclear sub-layer. The retinal layer  202  also includes an external limiting membrane and a photoreceptor sub-layer. The opaque layer  206  includes the retinal pigment epithelium (RPE) and the choroid. 
         [0026]    When therapeutic agents are delivered to the retina  104 , the fluid containing the therapeutic agents is delivered between the retinal layer  202  and the retinal pigment epithelium of the opaque layer  206 , i.e., in the subretinal space  204 . A fine needle is used to puncture the retinal layer  202  to allow the fluid containing the therapeutic agents into this subretinal space. A bleb is formed by the injection of a balanced salt solution (BSS), then a fluid containing therapeutic agents is injected into the space formed by the bleb. The formation of the bleb provides the space in which to inject the therapeutic agents without subject them to the fluid pressures necessary to form that space. In some embodiments, a single injection may be used to form the bleb and introduce the therapeutic agents. The fluid containing the therapeutic agents is introduced into the subretinal space  204  between the photo-receptor sub-layer and the retinal pigment epithelium, where immune system reactions to the therapeutic agents may be relatively subdued. 
         [0027]    Care must be taken to avoid puncturing the retinal pigment epithelium of the opaque layer  206  in the process. Because the retina  104  is often less than about 0.5 millimeters thick, ensuring the proper penetration depth may be difficult. Additionally, the volume of fluid containing the therapeutic agents is injected into the subretinal space  204 , back flow or reflux of the therapeutic agents from the bleb back through the puncture in the retinal layer  202  into the vitreous chamber  112  can potentially result in the formation of tumors from misplaced stem cells or in the loss of therapeutic agents, which may decrease the efficacy of treatment. Thus, the total volume of fluid injected should be controlled. 
         [0028]    The systems, devices, and methods of this disclosure, embodiments of which are described herein, may facilitate the proper positioning of the perforating tip of the fine needle in the retina  104 , may prevent reflux into the vitreous chamber, and may enable a single surgeon to perform the operation. 
         [0029]      FIG. 3  illustrates an exemplary retinal treatment system, generally designated as console  300 . The console  300  includes a base housing  302  with a computer unit  304  and an associated display screen  306  adapted to show data relating to system operation and performance during ophthalmic surgical procedures. The console  300  also includes a number of subsystems that may be used together to perform a vitrectomy surgical procedure prior to the injection of therapeutic agents in order to provide improved access to the retina. For example, the subsystems include a control system that has one or more of a foot pedal subsystem  308  including a foot pedal  310  having a number of foot actuated controls and a device control system or subsystem  312  in communication with a hand-held surgical instrument shown as delivery device  314 . Another subsystem may be used to provide tracking of a distal end of the delivery device  314 . This may be done using optical coherence tomography (OCT), by using a displacement sensor, or by other appropriate mechanisms. The tracking information and other information may be provided to the display screen  306  or to a surgical microscope heads-up display. Some embodiments of the console  300  may further include a vitrectomy cutter subsystem with a vitrectomy hand piece that can also be controlled using the foot pedal  310  and the device control subsystem  312 . These subsystems of console  300  may overlap and cooperate to perform various aspects of a procedure and may be operable separately and/or independently from each other during one or more procedures. That is, some procedures may utilize one or more subsystems while not using others. 
         [0030]    Referring now to  FIG. 4 , a subretinal delivery device  400  is illustrated in cross-section. The delivery device  400  may be used as the delivery device  314  of the console  300  of  FIG. 3 . The delivery device  400  includes an outer tube  402  and an inner tube or needle  404 . In exemplary some embodiments, the outer tube  402  is a 23 or 25 gauge needle, while the needle  404  is a finer gauge needle, such as a 38 gauge needle. Other sizes of outer tubes and needles may be used in other embodiments. The needle  404  is positioned within the outer tube  402  and extends beyond a distal end  406  thereof. 
         [0031]    A proximal end of the needle  404  is coupled to an actuatable chamber  408  which contains therapeutic agents, such as, for example, genes, stem cells, or other agents suspended in a fluid. When the chamber  408  is activated, a plunger  409  forces some or all of the fluid through the needle  404  and out a perforating distal tip  410  thereof. The plunger  409  of the chamber  408  may be activated mechanically, electrically, and/or pneumatically, under the control of the device control subsystem  312  of the console  300  of  FIG. 3 . The control subsystem  312  may communicate by a communication line to an actuator  411  that is coupled to drive the plunger  409 . In some embodiments, a pre-packaged cartridge of fluid containing therapeutic agents is provided for insertion into the chamber  408 . The plunger  409  may engage with the cartridge, in such embodiments, to controllable eject the contents through the needle  404 . In some embodiments, the subretinal delivery device includes a first chamber that contains a balanced salt solution for the formation of the bleb and a second chamber for the fluid containing the therapeutic agents, with both chambers being coupled to the needle  404 . Additionally, some embodiments of the pre-packaged cartridge may include a first portion containing the balanced salt solution, configured to be injected first, and a second portion containing the therapeutic agents, configured to be injected after the first portion. 
         [0032]    In the illustrated embodiment of the subretinal delivery device  400 , a tip structure  412  is sealingly coupled to the distal end  406  of the outer tube  402 . The tip structure  412  is coupled to the outer tube  402  such that any fluid in the central lumen of the outer tube  402  does not leak out. A distance D is labeled in  FIG. 4  between the perforating distal tip  410  of the needle  404  and a distal end of the tip structure  412 . This distance D may be a desired penetration depth at which therapeutic agents are to be delivered into the subretinal space  204 , and thus may be approximately the distance through the retinal layer  202 . Distance D may range from about 100 to about 350 microns or more. In some embodiments, the distance D is controlled by the console  300  and can be adjusted by a surgeon using an interface provided thereby. In some instances, a surgeon may determine the thickness of the retinal layer  202  using optical coherence tomography or another technique before using the interface to select the appropriate distance D. The console  300  communicates with the subretinal delivery device  400  to move the needle  404  as needed. While the perforating distal tip  410  is sharpened for penetration through the retinal layer  202  of the eye  100 , the broader surface area of the distal end of the tip structure  412  may act to inhibit further penetration of the delivery device  400  into the subretinal space, preventing a surgeon from puncturing the RPE and missing the subretinal space. 
         [0033]    The illustrated embodiment of the delivery device  400  also includes a sealing gel chamber  414 . Like the chamber  408 , the sealing gel chamber  414  may be actuated mechanically, electrically, or pneumatically by the plunger  409  controlled by the control system of console  300  of  FIG. 3 . Unlike the chamber  408 , the sealing gel chamber  414  contains a tissue sealant or sealing gel instead of therapeutic agents. The chamber  414  is actuated to expel the sealing gel into a chamber  416  formed by the outer tube  402 , the tip structure  412 , and a barrier wall  418 . As illustrated, the sealing gel is a hydrogel that is cohesive and adheres to the tissue of the retina. Once the chamber  416  is filled, additional sealing gel introduced from the chamber  414  is force out of one or more openings through the distal end  406  of the outer tube. In the illustrated embodiment featuring the tip structure  412 , two such openings are depicted: opening  420 A and opening  420 B. Some embodiments may include an annular opening or more include more than three openings. 
         [0034]    Either before or during contact between the distal end of the tip structure  412  and the limiting membrane of the retinal layer  202 , a volume of sealing gel is expelled from the sealing gel chamber  414  into contact with the retinal layer  202 . The sealing gel provides or enhances a seal between the delivery device  400  and the retina  104  such that when the chamber  408  is actuated, to form a bleb and/or to inject the therapeutic agents, reflux of the therapeutic agents into the vitreous chamber  112  is inhibited or eliminated. 
         [0035]    As illustrated in  FIG. 4 , both of the chambers  408  and  414  are included in a housing  422 . The housing  422  may be shaped and sized to fit in the hand of a surgeon performing the retinal treatment. Although the chamber  408  is illustrated as positioned within the outer tube  402 , in some embodiments the chamber  408  may be situated elsewhere in the housing  422 . 
         [0036]    By using the console  300  of  FIG. 3 , including the footswitch  308 , a single surgeon may position the delivery device  400  such that the distal tip  410  of the needle  404  is positioned desirably in the subretinal space and, while maintaining the positioning of the delivery device  400 , trigger the actuation of the therapeutic fluid chamber  408  and the sealing gel chamber  414  to inject the controlled, predetermined volume of fluid containing therapeutic agents and to prevent reflux of those agents. 
         [0037]    In some embodiments, the delivery device  400  further includes a knob  424  configured on the housing  422  of the delivery device  400 . The knob  424  may be a slider or a wheel-type knob that is mechanically coupled to the inner tube  404 , such that by manipulating the knob  424 , the inner tube  404  may be moved relative to the outer tube  402 . For example, in some embodiments, the inner tube  404  may be advanced relative to the outer tube  402  and into a subretinal space, through the retinal layer  202 . In some additional embodiments, the knob  424  may provide for a plurality of detent positions, such that when the knob is moved from one detent position to another, the inner tube  404  is moved relative to the outer tube by a known distance, such as by 25 microns. Thus, a desired distance D can be selected by moving the knob  424  an appropriate number of detent positions. 
         [0038]      FIGS. 5A-F  illustrate a plurality of embodiments of the distal end of the delivery device  400 .  FIG. 5A  illustrates the outer tube  402  having an abrupt distal end  406  that abuts the needle  404 , which protrudes beyond the distal end  406  by a distance D as seen in  FIG. 4 .  FIG. 5B  illustrates a distal end  510  that is similar to the distal end  500  of  FIG. 5A . The distal end  510  further includes two openings  502 A and  502 B. Other embodiments may include more or fewer openings. The openings  502 A and  502 B permit a tissue sealant or sealing gel to be expelled from the lumen of the outer tube  402  toward the tip of the needle  404 , thereby providing or improving a seal at the puncture site.  FIG. 5C  illustrates a distal end  520 . The distal end  520  shares many of the features illustrated in the distal end  500  of  FIG. 1A , but further includes a soft cap  504  affixed to the distal end  406  of the inner tube  402 . The soft cap  504  may be made from a plastic or polymer material such as silicone, and may provide a seal when engaged with or compressed against the retina  104 , conforming thereto, thereby preventing reflux. 
         [0039]      FIGS. 5D-F  are also cross-sectional illustrations of embodiments of distal ends of a delivery device  400 .  FIG. 5D  illustrates a distal end  530  that has a frustoconical tip structure  506  extending from about the distal end  406  of the outer tube  402 . The tip structure  506  may be formed from a soft material that deforms somewhat when compressed against the retina  104  of the eye  100 . The distal end  540  illustrated in  FIG. 5E  is similar to that of  FIG. 5D , but the distal end of the tip structure  508  has a terminal surface that is slanted such that it is not orthogonal to the needle  404  running therethrough. Similarly, the tip  410  of the needle  404  is slanted. This may decrease an amount of force necessary to puncture the retinal layer  202  of the retina  104 .  FIG. 5F  illustrates a distal end  550  of a delivery device  400 . The distal end  550  includes a tip structure  511 , which is similar to the tip structure  506  of  FIG. 5D . However, the tip structure  511  includes two illustrated openings  512 A and  512 B, through which a sealing gel  514  may be injected to form a seal or enhance the seal formed by the tip structure  511  flexing to conform to the surface of the retina  104 . The various features of the distal ends of the delivery device  400 , as illustrated in  FIGS. 5A-F , may be combined in additional embodiments. 
         [0040]    Referring now to  FIGS. 6A and 6B , which are side-view illustrations of embodiments of the delivery device  400  of  FIG. 4 . The distal end of the delivery device  400  shown in  FIG. 6A  is similar to the distal end  520  of  FIG. 5C , although as seen in  FIG. 6A , the needle  404  has an angled tip  410 .  FIG. 6A  illustrates the delivery device  400  as inserted into a retina  104  as depicted in  FIG. 2 . As illustrated, the needle  404  extends beyond a soft cap  504  positioned at the distal end of the outer tube  402 . The needle  404  extends a distance such that the tip  410  is in the subretinal space  204 . By holding the delivery device in contact with the surface of the retina  104  and applying slight pressure, the soft cap  504  conformingly compresses against the surface of the retina  104  to form a seal. The seal prevents back flow or reflux of injected fluid containing therapeutic agents, thereby preventing the therapeutic agents from entering the vitreous chamber  112 . 
         [0041]      FIG. 6B  illustrates another mechanism for providing a seal to prevent reflux. The distal end  406  of the delivery device  400  in  FIG. 6B  is a distal end  510  illustrated in  FIG. 5B  and described herein. The distal end includes one or more holes such that a sealing gel  602  may be expelled therefrom to provide the seal. In some embodiments, the sealing gel  602  is a predetermined volume of sealing gel expelled from the delivery device  400  in a controlled manner after being triggered by the surgeon. The sealing gel  602  may be expelled prior to contact between the outer tube  402  and the surface of the retina  104 . The soft cap  504  and the sealing gel  602  may both serve to provide a predictable separation distance between the distal end of the outer tube  402  and the distal tip  410  of the needle  404 . For example, the separation distance may be about 250 microns or more such that when the therapeutic agents are injected into the subretinal space  204 , they are injected in the optimal location. 
         [0042]    Referring now to  FIGS. 7A ,  7 B, and  7 C, these figures illustrate embodiments of a subretinal therapeutic agent delivery device have a force moderation structure. In  FIG. 7A , a portion of delivery device  700  is depicted in cross-section. The delivery device  700  includes an outer tube  702  having a lumen  704  therein. A distal end  706  of the outer tube  702  includes a tip structure  708  affixed therein. Through a hole in the center of the tip structure  708  runs a needle  710  extending a distance there from. The needle  710  extends through the lumen  704  to a chamber  712  which contains therapeutic agents suspended in a fluid. A plunger  714  is coupled to the chamber  712  to eject the volume of fluid from the chamber  712  when subjected to an activation or actuation energy. As illustrated, the lumen  704  further includes a spring or biasing element  716 . As illustrated, the biasing element  716  is coupled to the needle  710  by a coupling member  718  on one side and contacts a ring  720  that protrudes inwardly from the inner surface of the outer tube  702 . By selecting an appropriate spring constant of the biasing element  716 , a force applied by the needle  710  on the components of a retina may be limited so as to prevent a surgeon from puncturing the retinal pigment epithelium while permitting the surgeon to puncture the limiting membrane of the retina, thereby accessing the subretinal space. The force required to puncture the RPE is greater than the force required to puncture the limiting membrane. In this way, the biasing element  716  serves as a force moderation structure. Then, by actuating the chamber  710  with the plunger  714 , the desired volume of fluid containing therapeutic agents may be injected into the subretinal space. 
         [0043]      FIG. 7B  is a cross-sectional illustration of a delivery device  730 , which shares a number of features in common with a delivery device  700  as described herein, but includes a different force moderation structure. As illustrated in  FIG. 7B , the delivery device  700  includes an outer tube  702  having a lumen  704  therein. A distal end  706  of the outer tube  704  is coupled to a tip structure  708 . The needle  732  is inserted through the lumen  704  and through the tip structure  708  such that the needle  732  may be moved along the axis of the outer tube  702 . Unlike the delivery device  700  which included a spring  716  as a biasing element, the needle  732  provides a spring constant by including a biasing element that is a corrugated section  734 , having an accordion-like cross-section. The corrugated section  734  of the needle  732  allows the needle  732  to compress when subjected to a certain degree of force. For example, the corrugated section  734  may compress when the needle  732  is pushed against the retinal pigment epithelium, thereby preventing the needle  732  from puncturing the RPE. Thereby, the corrugated section  734  may provide a force moderation structure. 
         [0044]      FIG. 7C  is a cross-sectional illustration of a delivery device  750  that shares many of the features of the delivery devices  730  and  700 , but includes a different force moderation structure. In the delivery device  750  the chamber  712  and the plunger  714  are positioned within a rigid coupler  752 . The rigid coupler  752  contains the chamber  712  and rigidly couples the chamber  712  to the needle  710 . The rigid coupler  752  may be coupled to an actuator, such as a mechanical or pneumatic actuator, that may rapidly move the needle  710  forward a predetermined distance, with the plunger  714  able to move independently of the rigid coupler  752  as provided by an actuator  715 . For example, when the delivery device  750  is brought into contact with the retina by a surgeon, a tip of the needle  710  may be positioned within the tip structure  708 . By triggering the actuator  715 , such as by tapping a switch on a foot pedal or otherwise using a control system, the surgeon may cause the rigid coupling  752  and the needle  710  to be forced forward a predetermined distance greater than the thickness of the retinal layer  202  but less than the distance from the inner surface of the limiting membrane to the RPE. Thus, the mechanical or pneumatic actuator coupled to the rigid coupler  752  may position the tip of the needle  710  desirably within the subretinal space. 
         [0045]      FIGS. 8A and 8B  are cross-sectional illustrations of a distal end of a delivery device  800 , similar in appearance to that shown in  FIG. 4 .  FIG. 8A  illustrates the delivery device  800  in a retracted state, while  FIG. 8B  illustrates the delivery device  800  in an extended state. The delivery device  800  includes an outer tube  802  having a lumen  804  extending therethrough. A distal end of the outer tube  802  is coupled to a tip structure  806  that has a needle  808  moveably inserted therein. The needle  808  is formed from a memory material that causes the needle  808  to be curved in a natural state. While the tip  810  of the needle  808  is positioned within the tip structure  806 , the tip  810  remains substantially straight as illustrated in  FIG. 8A . When the tip  810  of the needle  808  is extended beyond the tip structure  806 , the natural shape of the memory material of the needle  808  becomes apparent as seen in  FIG. 8B . As illustrated, the tip  810  in a natural state may have a radius of curvature ranging from about 100 microns to about 350 microns or more. Other embodiments of the tip  810  of the needle  808  of the delivery device  800  may have a larger or smaller radius of curvature. Embodiments of delivery devices having needles that curve when extended beyond a tip structure may avoid puncturing the retinal pigment epithelium by preventing any contact between a tip of the needle and RPE. In some embodiments, the memory material is a shape memory alloy, a polymer, or other material. 
         [0046]    By controlling the depth and angle of entry of the fluid containing therapeutic agents into the subretinal space, the stresses applied to the therapeutic agents may be decreased. When therapeutic agents flow from a chamber through a needle, out of a tip thereof, and into the layers of the subretinal space, the therapeutic agents are exposed to sheering stresses that may damage them, decreasing the efficacy of treatment. The sheering stresses may be mitigated by shaping the tip of the injecting needle. For example, the curved tip  810  as the delivery device  800  may lower the sheering stresses. Also, having a beveled or angled tip of the injecting needle may decrease the sheering stresses. In order to decrease the stresses experienced while flowing through the injecting needle, the inside surface of the needle may be treated to decrease friction. For example, the injecting needles as disclosed herein in delivery devices  400 ,  800 , and others, may have their inside surfaces coated with Teflon® or a similar friction-reducing coating. The tip of injecting needles may also impact the distribution of therapeutic agents into the subretinal space providing a bleb with a larger or smaller footprint. 
         [0047]      FIG. 9  is a flowchart of a method  900  of delivering therapeutic agents into a retina of an eye a patient. As illustrated in  FIG. 9 , the method  900  includes several enumerated steps. However, embodiments of method  900  may include additional steps before, after, in between, and/or as part of the enumerated steps. Thus, method  900  may begin in step  902  in which a surgeon introduces a retinal treatment device into a vitreous chamber of the eye. The retinal treatment device may be a delivery device like the delivery device  400  of  FIG. 4 , or another delivery device described herein, and may be part of a retinal treatment system like the console  300  illustrated in  FIG. 3 . The surgeon may insert the delivery device  400  through the sclera of the eye into the vitreous chamber. Additional procedures, such as a vitrectomy procedure may be performed earlier. 
         [0048]    In step  904 , the surgeon positions the retinal treatment device in contact with the retina so as to form a seal between the retinal treatment device and the retina. This may be accomplished in several ways. As illustrated in  FIG. 6A , a soft cap may be coupled to the distal end of the outer tube of a delivery device after the needle of the retinal treatment device punctures the limiting membrane of the retina. By applying slight pressure with the delivery device, the surgeon causes the soft cap to conform to the upper surface of the retina, thereby forming a seal. In some embodiments of the method  900 , the surgeon forms the seal between the retinal treatment device and the retina by expelling a tissue sealant or sealing gel from the distal end of the delivery device. The sealing gel forms a seal between the retina and the retinal treatment device, preventing reflex of the fluid containing the therapeutic agents back into the vitreous chamber. Combinations of these sealing techniques may be employed by the surgeon in some embodiments. 
         [0049]    In step  906 , an injection routine is activated to introduce therapeutic agents into a subretinal space. The surgeon may trigger the injection routine by using the foot pedal  310  of the foot pedal subsystem  308  coupled to the console  300 . The foot pedal  310  sends a signal to the console  300 , which is interpreted by the console as an instruction to activate an actuator, such as the actuator  408  of the delivery device  400 . Thus, the console  300  may control the injection of therapeutic agents by controlling the actuator  408 . The injection routine may control a flow rate in addition to a volume of fluid and/or a sheer stress applied to the therapeutic agents. The console  300  may provide for the selection of predetermined values using an interface. The injection routine may also control an injection pressure. Additionally, embodiments of the injection routine as included in method  900  may activate a needle penetration action. For example, the console  300  may instruct the actuator  752  of the delivery device  750  as illustrated in  FIG. 7C . Alternatively, the housing  422  may include a knob for inserting the needle in a controlled manner. The knob may be a continuous or stepped knob, in which case each step may move the needle a constant amount, such as 10 or 25 microns. The injection routine may include an initial step of forming a bleb with fluid not containing therapeutic agents, such as a balanced salt solution or saline solution, prior to injecting the therapeutic agents. For example 100 microliters of the balanced salt solution may be injected to form the bleb. This may provide improved dispersion of the therapeutic agents and may prevent damage to the therapeutic agents from the higher pressures associated with bleb formation. 
         [0050]    In step  908 , the surgeon withdraws the retinal treatment device from the vitreous chamber. In embodiments in which a sealing gel is used, the sealing gel may remain in contact with the retina continuing to inhibit or prevent reflux, and then be removed over time by the natural processes of the eye. A replacement fluid may be introduced into the vitreous chamber of the eye to replace vitreous humor removed as part of the retinal treatment. 
         [0051]    Method  900 , in conjunction with the systems and delivery devices described herein may facilitate the injection of therapeutic agents into subretinal space by a single surgeon. Because the system permits actuation of the injection of fluid by the surgeon holding the delivery device, such as by selecting a footswitch that is part of a control system, a second surgeon or an assistant may not be needed. Embodiments of delivery devices described herein may prevent or reduce the likelihood of puncturing of the retinal pigment epithelium (RPE) and may control the introduction of the therapeutic agents into the space to minimize sheering stresses and improve distribution, thereby improving efficacy. 
         [0052]    Persons of ordinary skill in the art will appreciate that the embodiments encompassed by the present disclosure are not limited to the particular exemplary embodiments described above. In that regard, although illustrative embodiments have been shown and described, a wide range of modification, change, combination, and substitution is contemplated in the foregoing disclosure. It is understood that such variations may be made to the foregoing without departing from the scope of the present disclosure. Accordingly, it is appropriate that the appended claims be construed broadly and in a manner consistent with the present disclosure.