Patent Publication Number: US-2023145887-A1

Title: Ophthalmic implant for delivering therapeutic substances

Description:
CROSS-REFERENCE TO PRIORITY DOCUMENT 
     This application is a continuation of U.S. patent application Ser. No. 16/514,128 filed Jul. 17, 2019, which is a continuation of U.S. patent application Ser. No. 15/386,586 filed Dec. 21, 2016, now U.S. Pat. No. 10,398,593, which is a continuation of U.S. patent application Ser. No. 14/228,130, filed Mar. 27, 2014, now U.S. Pat. No. 9,526,654, which claims the benefit of priority of U.S. Provisional Patent Application Ser. No. 61/806,267, filed Mar. 28, 2013, the full disclosures of which are hereby fully incorporated by reference. 
    
    
     BACKGROUND 
     Diseases that affect vision can be treated with a variety of therapeutic agents, but the delivery of drugs to the eye continues to be challenging. Injections of therapeutic via the eye can be painful, involve some risk of infection, hemorrhage and retinal detachment. Depending on the frequency, intra-ocular injections can be time-consuming for both patient and physician. Consequently, in at least some instances the drug may be administered less often than the prescribed frequency resulting in sub-optimal treatment benefit. Further, bolus intra-ocular injections may not provide the ideal pharmacokinetics and pharmacodynamics. A bolus injection of drug into the vitreous humor of a patient can result in a peak drug concentration several times higher than the desired therapeutic amount and then before the patient is able to get the next injection drop to a drug concentration that is far below therapeutic effectiveness. 
     SUMMARY 
     In one aspect, disclosed is an implantable therapeutic device to treat a patient. The device includes a hollow refillable housing for implantation within the posterior segment of an eye through a penetration in the sclera of the eye. The housing has a proximal end region. A proximal retention structure protrudes outward from the proximal end region and has an access portion opening. A penetrable barrier is positioned at least in part within the access portion opening and is configured to be repeatedly penetrated. A rigid porous structure is positioned within a region of the housing away from the access portion opening. A reservoir chamber extends along an axis between the penetrable barrier and the porous structure. The reservoir chamber includes a volume sized to deliver therapeutic amounts of a therapeutic agent to the eye for an extended period of time. The access portion opening opens into the reservoir chamber. A cover is coupled to at least an upper surface of the proximal retention structure. 
     In some variations, one or more of the following can optionally be included in any feasible combination in the above methods, apparatus, devices, and systems. 
     The access portion opening can be over-molded by the cover. The cover can encapsulate and bond the proximal retention structure and an upper surface of the penetrable barrier can be positioned within the access portion opening. The cover can encapsulate and bond to at least an upper surface of the proximal retention structure. The cover can encapsulate and bond to a lower surface of the proximal retention structure. The cover can maintain a seal of the reservoir chamber volume. The cover and the proximal retention structure can have the same shape profile. The cover and the penetrable barrier can be penetrated during filling of the reservoir chamber. The cover and the penetrable barrier can be configured to reseal after penetration of the reservoir chamber. The proximal retention structure can include one or more through-holes. The penetrable barrier can be pre-molded and the cover can be over-molded. The penetrable barrier can be a soft, high strength material and the cover can be a high durometer material. The cover can be a translucent material. The device can further include an anchor positioned within the access portion opening and in contact with at least a portion of the penetrable barrier. The penetrable barrier can further include a distal region that is flared and positioned within a proximal end region of the reservoir chamber. 
     In an interrelated aspect, disclosed is an implantable therapeutic device to treat a patient having a hollow refillable housing for implantation within the posterior segment of an eye through a penetration in the sclera of the eye. The housing has a proximal end region. A proximal retention structure is protruding outward from the proximal end region and includes an access portion opening. A penetrable barrier is positioned at least in part within the access portion opening. The penetrable barrier is configured to be repeatedly penetrated. A rigid porous structure is positioned within a region of the housing away from the access portion opening. A reservoir chamber extends along an axis between the penetrable barrier and the porous structure. The reservoir chamber has a volume sized to deliver therapeutic amounts of a therapeutic agent to the eye for an extended period of time. The access portion opening opens into the reservoir chamber. An anchor is positioned within the access portion opening and in contact with at least a portion of the penetrable barrier. 
     In some variations, one or more of the following can optionally be included in any feasible combination in the above methods, apparatus, devices, and systems. 
     The penetrable barrier can be pre-molded with soft, high strength material. The anchor can be formed of a high durometer material that resists deformation. The penetrable barrier can be bonded to the anchor creating a single septum structure. The anchor can engage an undercut feature in the proximal end of housing. The penetrable barrier can apply radial compression to the anchor. The device can further include a cover covering an upper surface of the proximal retention structure. The device can further include a sealing element positioned within a proximal end region of the reservoir chamber and coupled to the penetrable barrier. 
     More details of the devices, systems and methods are set forth in the accompanying drawings and the description below. Other features and advantages will be apparent from the description and drawings 
    
    
     
       BRIEF DESCRIPTION OF THE DRAWINGS 
       These and other aspects will now be described in detail with reference to the following drawings. Generally speaking the figures are not to scale in absolute terms or comparatively but are intended to be illustrative. Also, relative placement of features and elements may be modified for the purpose of illustrative clarity. 
         FIG.  1    is a cross-sectional, schematic view of a portion of the human eye; 
         FIG.  2    is a cross-sectional, schematic view of a portion of the human eye having an implementation of a therapeutic device implanted therein; 
         FIG.  3 A  is an exploded, perspective view of an implementation of a therapeutic device; 
         FIGS.  3 B- 3 C  are exploded, side views of the therapeutic device of  FIG.  3 A ; 
         FIGS.  3 D- 3 E  are top and bottom views, respectively, of the therapeutic device of  FIG.  3 A ; 
         FIG.  3 F  is a side, cross-sectional view of the therapeutic device of  FIG.  3 A ; 
         FIGS.  4 A- 4 B  are perspective and cross-sectional partial views, respectively, of an implementation of a therapeutic device; 
         FIG.  5    is a side, cross-sectional partial view of an implementation of a therapeutic device; 
         FIG.  6   . is a side, cross-sectional partial view of an implementation of a therapeutic device. 
     
    
    
     DETAILED DESCRIPTION 
     Described herein are implantable devices, systems and methods of use for the delivery of one or more therapeutics for the treatment of diseases. The devices and systems described herein can deliver therapeutics to select regions and structures of the body over a variety of periods of time. 
     The devices and systems described herein have improved penetrable access portions for the repeated injection and long-term treatment and implantation of the device. It should be appreciated that the penetrable access portions as described herein can be used with a number of various different implantable therapeutic devices including one or more of those devices described U.S. Pat. Nos. 8,399,006; 8,623,395; PCT Pat. Publication No. WO2012/019136; PCT Pat. Publication No. WO2012/019047; and PCT Pat. Publication No. WO 2012/065006; the entire disclosures of which are incorporated herein by reference thereto. 
     Eye Anatomy 
       FIG.  1    is a cross-sectional, schematic view of a portion of the human eye showing the anterior chamber, posterior chamber and vitreous body of the eye. The eye  10  is generally spherical and is covered on the outside by the sclera  24 . The retina  26  lines the inside posterior segment of the eye  10  and includes the macula  32 . The retina  26  registers the light and sends signals to the brain via the optic nerve. The bulk of the eye  10  is filled and supported by the vitreous body (vitreous humor)  30 , a clear, jelly-like substance disposed between the lens  22  and the retina  26 . The elastic lens  22  is located near the front of the eye  10 . The lens  22  provides adjustment of focus and is suspended within a capsular bag from the ciliary body  20 , which contains the muscles that change the focal length of the lens  22 . A volume in front of the lens  22  is divided into two by the iris  18 , which controls the aperture of the lens  22  and the amount of light striking the retina  26 . The pupil is a hole in the center of the iris  18  through which light entering anteriorly passes. The volume between the iris  18  and the lens  22  is the posterior chamber. The volume between the iris  18  and the cornea  12  is the anterior chamber. Both chambers are filled with a clear liquid known as aqueous humor. 
     The cornea  12  extends to and connects with the sclera  24  at a location called the limbus  14  of the eye. The conjunctiva  16  of the eye is disposed over the sclera  24  and the Tenon&#39;s capsule (not shown) extends between the conjunctiva  16  and the sclera  24 . The eye  10  also includes a vascular tissue layer called the choroid  28  that is disposed between a portion of the sclera  24  and the retina  26 . The ciliary body  20  is continuous with the base of the iris  18  and is divided anatomically into pars plica and pars plana, a posterior flat area approximately 4 mm long. The pars plana region  25  is an example of a region of the eye suitable for placement and retention of the devices described herein. The eye  10  can include an insertion of the tendon of the superior rectus muscle to couple the sclera  24  of the eye to the superior rectus muscle. The devices described herein can be positioned in many locations of the pars plana region  25 , for example away from tendon of the superior rectus muscle and one or more of posterior to the tendon, anterior to the tendon, under the tendon, or with nasal or temporal placement of the therapeutic device. 
       FIG.  2    shows an implementation of the therapeutic device  100  implanted at the pars plana region  25 . The device  100  can be positioned so as to extend from the pars plana region  25  through the sclera  24  into the posterior segment of the eye including the vitreous body  30  so as to release the therapeutic agent into the vitreous body  30 . The therapeutic device  100  can include a proximal, retention structure  120 , such as a smooth protrusion at a proximal end region of the device  100 , configured for placement along the sclera  24 . In some implementations, the retention structure  120  can be positioned under the conjunctiva  16  such that the conjunctiva  16  can cover the therapeutic device and protect the therapeutic device  100 . When the therapeutic agent is inserted or injected into the device  100 , the conjunctiva  16  may be lifted away, incised, or punctured with a needle to access the therapeutic device  100 . 
     It should be appreciated that the devices and systems described herein can be positioned in many locations of the eye and need not be implanted specifically as shown in the figures or as described herein. The devices and systems described herein can be used to deliver therapeutic agent(s) for an extended period of time to one or more of the following tissues: intraocular, intravascular, intraarticular, intrathecal, pericardial, intraluminal and intraperitoneal. Although specific reference is made below to the delivery of treatments to the eye, it also should be appreciated that medical conditions besides ocular conditions can be treated with the devices and systems described herein. For example, the devices and systems can deliver treatments for inflammation, infection, and cancerous growths. Any number of drug combinations can be delivered using any of the devices and systems described herein. 
     It should be appreciated that the devices and systems described herein can incorporate any of a variety of features described herein and that elements or features of one implementation of a device and system described herein can be incorporated alternatively or in combination with elements or features of another implementation of a device and system described herein as well as the various implants and features described in U.S. Pat. Nos. 8,399,006; 8,623,395; PCT Pat. Publication No. WO2012/019136; PCT Pat. Publication No. WO2012/019047; and PCT Pat. Publication No. WO 2012/065006. For example, the septum features described herein may be used with any of the various implementations of a device or system. For the sake of brevity, explicit descriptions of each of those combinations may be omitted although the various combinations are to be considered herein. Additionally, described herein are different methods for implantation and access of the devices. The various implants can be implanted, filled, refilled etc. according to a variety of different methods and using a variety of different devices and systems. Provided are some representative descriptions of how the various devices may be implanted and accessed, however, for the sake of brevity explicit descriptions of each method with respect to each implant or system may be omitted. 
     Implants 
     In a first implementation and as shown in  FIGS.  3 A- 3 F , the device  100  can include a housing  130 , a penetrable barrier  140  and a porous structure  150 . The housing  130  can be a rigid, hollow refillable housing for implantation within an interior chamber of the eye, such as the posterior segment of an eye through a penetration in the sclera of the eye. The housing  130  can have a proximal end region and a distal end region. The housing  130  can have an inner surface that defines, at least in part, a reservoir chamber  160  for holding a therapeutic material or agent(s) (see  FIG.  3 F ). The penetrable barrier  140  can be positioned within a proximal end region of the housing  130  such as within an opening  180  in an access portion of the device that leads into a reservoir chamber  160  of the device. The porous structure  150  can be positioned within another region of the housing  130  a distance away from the penetrable barrier  140  such as within an opening  152  leading out of the reservoir chamber  160  of the device. For example, the porous structure  150  can be positioned near a distal end region of the housing  130  opposite the location of the more proximal penetrable barrier  140 . The reservoir chamber  160  can have a volume sized to deliver therapeutic amounts of therapeutic agent to the eye for an extended period of time and the porous structure  150  can be configured to release therapeutic agent contained within the reservoir chamber  160  over the extended period of time. The housing  130  can include a retention structure  120  that can protrude outward from the proximal end region of the housing  130 . The access portion opening  180  can be an opening in the device  100  that extends into the reservoir chamber  160 . The penetrable barrier  140  can be positioned, at least in part, within the access portion opening  180  such that it forms a seal with the proximal end region of the housing  130 . As will be described in more detail below, the devices described herein can also include a cover  110  coupled to at least a region of the device such as the retention structure  120 . The cover  110  can cover, coat, cap, encapsulate, bond or otherwise couple to at least the penetrable barrier  140  of the device. The cover  110  can be configured to improve the integrity of the penetrable barrier  140  and its sealing engagement within the access portion opening  180  for repeated injection and long-term implantation. 
     Again with respect to  FIGS.  3 A- 3 F  and as mentioned above, a distal end region of the housing  130  can include another opening  152 , for example opposite the proximal access portion opening  180  into the reservoir chamber  160 , that extends between the inside of the reservoir chamber  160  out of the housing  130 . The porous structure  150  can be coupled to or positioned, at least in part, within the opening  152 . It should be appreciated that the porous structure  150  can be coupled to or positioned within other regions besides the distal end region of the housing  130 . The porous structure  150  can be affixed within an opening  152  in distal end of housing  130 , for example with glue or other material(s). Alternatively or in combination, the distal end of the housing  130  can include an inner diameter sized to receive the porous structure  150 , and the housing  130  can include a stop to position the porous structure  150  at a predetermined location on the distal end so as to define a predetermined size of reservoir chamber  160 . 
     Still with respect to  FIGS.  3 A- 3 F , the reservoir chamber  160  within the housing  130  of the device  100  can extend along axis  100 A between the penetrable barrier  140  positioned proximally within the access portion opening  180  to the location of the porous structure  150 . Therapeutic formulations injected into device  100  can be released from the reservoir chamber  160  in accordance with the volume of the reservoir chamber  160  and a release characteristic or release rate index of the porous structure  150 . The volume of the reservoir chamber  160  can be sized to deliver therapeutic amounts of a therapeutic agent to the eye for an extended period of time. The volume of the reservoir chamber  160  can be substantially determined by an inner cross sectional area of the housing  130 , such as the distance between the proximal, penetrable barrier  140  and the porous structure  150 . The release rate index (RRI) can be used to determine the release of the therapeutic from the device  100 . RRI encompasses (PA/FL) where P comprises the porosity, A comprises an effective area, F comprises a curve fit parameter corresponding to an effective length and L comprises a length or thickness of the porous structure  150 . Additional details regarding release characteristics of the porous structure  150  that can be used in the various devices described herein can be found, for example, in PCT Publication No. WO 2012/065006, which is incorporated herein by reference in its entirety. 
     The housing  130  can have a dimension such that its length generally exceeds its width or diameter. The housing  130  can have a diameter sized within a range, for example, from at least about 0.5 mm to at least about 4 mm, from at least about 1 mm to at least about 3 mm. In some implementations the diameter of the housing  130  at its widest point can be about 2 mm, for example. The housing  130  can have a length sized so as to extend from the conjunctiva  16  to the vitreous body  30  along axis  100 A to release the therapeutic agent into the vitreous body  30 . The housing  130  can have a length sized within a range, for example, from at least about 2 mm to at least about 14 mm, from at least about 4 mm to at least about 10 mm. In some implementations, the length of the housing  130  can be about 7 mm, for example. The above dimensions are provided as example dimensions and are not intended to be limiting. It should be appreciated that a variety and combination of dimensions are to be considered herein. 
     The housing  130  and reservoir chamber  160  can each (although not necessarily both) have an elliptical or oval cross-sectional shape, for example. This elongation of the device along one direction can allow for increased drug in the reservoir chamber  160  with a decrease interference in vision, for example, as the major axis of the ellipse can be aligned substantially with the circumference of the pars plana region  25  of the eye extending substantially around the cornea  12  of the eye, and the minor axis of the ellipse can be aligned radially with the eye so as to decrease interference with vision as the short axis of the ellipse extends toward the optical axis of the eye corresponding to the patient&#39;s line of sight through the pupil. Although reference is made to an elliptical or oval cross-section, many cross-sectional sizes and shapes can be used such as circular, square or rectangular with a short dimension extending toward the pupil of the eye and the long dimension extending along the pars plana of the eye. 
     One or more regions of the housing  130  of the devices described herein can be formed of a substantially rigid, biocompatible material. In some implementations, the walls of the housing  130  including at least the proximal retention structure  120  down to and including the porous structure  150  are substantially rigid such that the reservoir chamber  160  has a substantially constant volume when the therapeutic agent is released from the device so as to maintain a stable release rate profile, for example when the patient moves. The reservoir chamber  160  can remain substantially rigid and have a substantially constant volume even during injection of the therapeutic agent into the device, for example a device already implanted in the eye. 
     One or more regions of the housing  130 , one or more regions of the retention structure  120  as well as other portions of the devices described herein, alone or in combination, can be formed of one or more of many biocompatible materials including, but not limited to materials such as acrylates, polymethylmethacrylate, siloxanes, metals, titanium stainless steel, polycarbonate, polyetheretherketone (PEEK), polyethylene, polyethylene terephthalate (PET), polyimide, polyimide-imide, polypropylene, polysulfone, polyurethane, polyvinylidene fluoride, polyphenylene polyphenylsulfone or PTFE, and others. Alternatively or in combination, one or more portions of the devices described herein, such as the housing  130 , can be formed at least in part from an optically transmissive material such that the housing  130  can be translucent or transparent, such that when the device  100  is loaded with therapeutic agent the reservoir chamber  160  can be visualized outside the patient prior to implantation, for example when injected with a formulation of therapeutic agent prior to implantation in the physician&#39;s office. This visualization of the reservoir chamber  160  can be helpful to ensure that the reservoir chamber  160  is properly filled with therapeutic agent by the treating physician or assistant prior to implantation. For example, transparency can enable visualization, for example, using an indirect ophthalmoscope, of the contents of the reservoir chamber  160  of an implanted device allowing one to confirm that no air is trapped in the device and/or verify the clarity of the device contents. A cloudy appearance, for example, may indicate that some degree of contamination, microbial or otherwise, has occurred. The biocompatible, optically transmissive materials can include one or more of acrylate, polyacrylate, methlymethacraylate, polymethlymethacrylate (PMMA), polyacarbonate, glass or siloxane. 
     The porous structure  150  can include one or more of a release control element, a release control mechanism, permeable membrane, a semi-permeable membrane, a material having at least one hole disposed therein, channels formed in a rigid material, straight channels, nano-channels, nano-channels etched in a rigid material, laser drilled holes, laser etched nano-channels, a capillary channel, a plurality of capillary channels, one or more tortuous channels, sintered material, sintered rigid material, sintered glass, sintered ceramic, sintered metal, sintered titanium, tortuous micro-channels, sintered nano-particles, an open cell foam or a hydrogel such as an open cell hydrogel. Porous structures considered herein are described in U.S. Pat. Nos. 8,399,006; 8,623,395; PCT Publication No. WO2012/019136; PCT Publication No. WO2012/019047; and PCT Publication No. WO 2012/065006; the entire disclosures of which are incorporated herein by reference thereto. 
     Again with respect to  FIGS.  3 A- 3 F  and as mentioned above, the retention structure  120  can protrude outward from the proximal end region of the housing  130 . At least a first surface of the retention structure  120  can be configured to contact the sclera  24  and, in some implementations, can be configured to contact the conjunctiva  16  on at least a second surface of the retention structure  120 . For example, at least a portion of the underside of the retention structure  120  can contact the sclera  24  and at least a portion of the upper side of the retention structure  120  can contact the conjunctiva  16 . In some implementations, the retention structure  120  can be configured to contact the sclera  24  such that the retention structure  120  is at least partially embedded within the thickness of the sclera  24  and does not necessarily sit on an upper surface of the sclera or the conjunctiva. 
     The retention structure  120  can include a narrowed portion  121  and a wider, flanged portion  122  extending proximally from the narrowed portion  121 . The narrowed portion  121  can have a cross-section sized to fit in an elongate incision or a puncture through the pars plana region  25  without causing gaping of the tissue near either end of the incision. For example, an incision can be made with a device having a straight, flat blade, for example a 3.2 mm blade. Penetrating the sclera with such a blade can result in exposed scleral tissue that may need to be sealed (e.g. 6.4 mm or 2×3.2 mm). A cross-sectional region of an implant positioned within the cut region of the sclera, for example having a perimeter of 6.4 mm and a diameter of about 2 mm, could open the wound such that there would be relatively large voids on either side of the device, for example about 2.2 mm between either side of the device and the farthest aspects of the exposed sclera. These voids can result in cut portions of the sclera remaining exposed and unsealed. The geometry of the narrowed portion  121  of the devices described herein can be designed to minimize the length of cut scleral tissue that remains exposed and/or unsealed. 
     The narrowed portion  121  can have a first cross-sectional distance across, or first dimensional width, and a second cross-sectional distance across, or second dimensional width, in which the first cross-sectional distance across is greater than the second cross-sectional distance across providing the narrowed portion  121  with an elongate cross-sectional profile. The elongate cross section of the narrowed portion  121  can be sized in many ways to fit the incision. The elongate cross section can have a first dimension longer than a second dimension and can have one or more of many shapes such as dilated slit, dilated slot, lentoid, oval, ovoid, or elliptical. It should also be appreciated that the narrowed portion  121  can have other cross sectional shapes, for example, a circular shape, if desired. The dilated slit shape and dilated slot shape can correspond to the shape assumed by the scleral tissue when cut and dilated. The lentoid shape can correspond to a biconvex lens shape. The elongate cross-section of the narrowed portion  121  can include a first curve along a first axis and a second curve along a second axis that is different than the first curve. The narrowed portion  121  can be sized and configured to receive the sclera  24  upon implantation in the eye  10  when the flanged portion  122  is positioned between the sclera  24  and the conjunctiva  16  and the distal end of the housing  130  extends into the vitreous body  30 . 
     Flanged portion  122  of the retention structure  120  can include a first distance across and a second distance across. The first distance across can be greater than the second distance across (see  FIGS.  3 B and  3 C , for example). The first distance across can result in the flanged portion  122  having a diameter greater than a largest diameter of the housing  130  (see e.g.,  FIG.  3 B ) whereas the second distance across can result in the flanged portion  122  having a diameter equal to or less than a largest diameter of the housing  130  (see e.g.,  FIG.  3 C ). The flanged portion  122  can have a variety of shapes, such as rectangular, square, oval, elliptical, circular, teardrop, polygonal or other shape. The flanged portion  122  can be formed as a smooth protrusion configured for placement along a portion of the sclera  24 . In some implementations, the flanged portion  122  is positioned under the conjunctiva  16 , such that the conjunctiva  16  covers and protects the device  100 . The flanged portion  122  can be formed from a translucent material such that the physician can visualize tissue under the flanged portion  122  to assess the patient and to decrease appearance of the device  100  when implanted. 
     As mentioned above, the penetrable barrier  140  can be positioned, at least in part, within access portion opening  180  sealing the reservoir chamber  160  on a proximal end region of the device  100 . The penetrable barrier  140  can be a septum configured to receive and be repeatedly penetrated by a sharp object such as a needle for injection of the therapeutic agent into the reservoir chamber  160 . The penetrable barrier  140  can be configured to re-seal when the sharp object is removed. The penetrable barrier  140  can be a pre-molded soft, high strength material. In some implementations, the penetrable barrier  140  can be formed from one or more elastic materials such as siloxane, rubber, or another liquid injection molding silicone elastomer such as NUSIL MED-4810 (NuSil Silicone Technology, Carpinteria, Calif.). In some implementations, the penetrable barrier  140  can include an opaque material and/or a colored material such that it can be visualized by the treating physician. 
     Repeated injection as well as long-term implantation of the device  100  can affect the integrity of the penetrable barrier  140 . For example, repeated injection through the penetrable barrier  140  can at least partially damage the device and negatively affect the seal between the inner surfaces of the housing  130 , retention structure  120  and the outer surfaces of the penetrable barrier  140 . Further, over time after implantation the penetrable barrier  140  can loosen relative to the housing  130 . Described herein are features to improve the integrity of the penetrable barrier  140 , its sealing engagement with the access portion opening  180  of the housing  130  and/or retention structure  120 , and the effectiveness of the access region for repeated injection and long-term implantation of the re-fillable devices described herein. 
     As described above and as best shown in  FIGS.  3 A- 3 F , the penetrable barrier  140  can be positioned within a proximal end region of the housing  130  at least in part within an opening of the access portion  180 . As such, the overall shape of the external surface of the penetrable barrier  140  can correspond generally to the shape of the surface(s) near the access portion opening  180  against which the penetrable barrier  140  contacts to mate and seal. It should be appreciated that the points of contact between the penetrable barrier  140  and the housing  130  can vary. The penetrable barrier  140  can make contact, for example sealing contact, with at least one or more surfaces or regions of the upper end of the reservoir chamber, the housing  130 , the retention structure  120 , the narrowed portion  121 , the flanged portion  122 , the access portion opening  180 , and/or a combination thereof. 
     As best shown in  FIGS.  3 B- 3 C , the penetrable barrier  140  can have an upper region  144 , a middle region  141 , and a distal region  142 . The upper region  144  can be sized to reside within and mate with at least a portion of the flanged portion  122 . The upper region  144  can form an upper surface of the penetrable barrier  140  available through the access region opening  180  of the device. In some implementations, the outer surface of the upper region  144  can be beveled to correspond with the shape of and provide optimum mating engagement with an inner surface of the retention structure  120  that can also be beveled (see  FIG.  3 F ). Engagement between the upper region  144  and the access portion opening  180  aids in forming a seal and retaining the penetrable barrier  140  within the access portion opening  180 . The middle region  141  can be sized to reside within and mate with an inner surface of the narrowed portion  121  of the retention structure  120 . As such, the middle region  141  can be a reduced diameter region or form a “waist” in the penetrable barrier  140 . Alternatively, the middle region  141  can be relatively annular and have a generally planar outer surface configured to contact a corresponding planar surface forming the opening of the access region  180 . 
     In some implementations, the distal region  142  can have a diameter that is the same as or greater than the narrowed portion  121  of the retention structure  120  such that the distal region  142  helps to prevent withdrawal of the penetrable barrier  140  out of the access region  180 . For example, the distal region  142  can have one or more tabs, a flared skirt, flange, rib or other feature of enlarged diameter compared to the middle and/or upper regions  141 ,  144  and sized to reside within and mate with at least a portion of the retention structure  120  located distal to the narrowed portion  121  and/or an upper region of the reservoir chamber  160  such as with an inner wall of the housing  130 . In some implementations, the flange can have an upper surface configured to contact an inner wall surface near the upper end of the reservoir chamber  160  that surrounds the opening  180  of the access portion. The features of the distal region  142  having an enlarged diameter compared to the middle or upper regions  144 ,  141 , such as the one or more tabs can also aid in forming a seal and retaining the penetrable barrier  140  within the access portion opening  180 . For example, as best shown in  FIG.  3 C , the distal region  142  of the penetrable barrier  140  can include a first tab  142   a  positioned on a first region of the penetrable barrier  140  and a second tab  142   b  positioned on a second region of the penetrable barrier  140 , such as a side opposite or a distance away from the first region. The tabs  142   a ,  142   b  can project away from the longitudinal axis  100 A providing a cross-sectional diameter of the penetrable barrier  140  in at least one direction that is greater that the cross-sectional diameter of the middle region  141 . The cross-sectional diameter of the penetrable barrier  140  distal to the middle region  141  in at least a first direction can be equal to, more or less than the cross-sectional diameter of the upper region  144 . It should be appreciated that the distal region  142  can have one, two, three, four, or more tabs spaced around the wall of the penetrable barrier  140 . It should also be appreciated that the entire distal region  142  of the penetrable barrier  140  can be flared away from the longitudinal axis  100 A of the penetrable barrier  140  as shown in  FIG.  4 B  to better engage an upper region of the housing  130  near the access region  180 . In further implementations, the distal region  142  of the penetrable barrier  140  can be include a flange of an enlarged diameter. It should be appreciated that the distal region  142  as well as the entire penetrable barrier  140  itself can have a variety of shapes and features that act to improve retention within the upper end of the reservoir chamber  160 . The features of one implementation of the penetrable barrier  140  can be used in combination or in the alternative with one or more implementations of the devices described herein. 
     The penetrable barrier  140  can be adhered within the device  100 , for example, in at least a portion of the access portion opening  180  of the retention structure  120 . Alternatively, the penetrable barrier  140  can be positioned into a proximal region of the device  100  in an adhesion-free manner and rely on the mating features between the external surface of the penetrable barrier  140  with the corresponding surfaces of the access portion opening  180  against which the penetrable barrier  140  abuts and seals. 
     As mentioned above, the devices described herein can be coupled to a cover  110  that can be configured to improve the integrity of the penetrable barrier  140  and its sealing engagement with the access portion opening  180  for repeated injection and long-term implantation. This provides a benefit to a device intended to be implanted long-term and re-filled while implanted, such as those described herein. The cover  110  can cap, coat, bond, encapsulate, cover, or otherwise couple to one or more components of the devices described herein. For example, at least a portion of a proximal end region of the device  100 , including one or more combinations of the upper surface of the penetrable barrier  140  positioned within the opening of the access portion  180 , an upper surface of the proximal retention structure  120  including the flanged portion  122 , a lower surface of the proximal retention structure  120  including the flanged portion  122 , the narrowed portion  121  of the retention structure  120 , and at least a portion of an outer surface of the housing  130  near the proximal end region. 
       FIGS.  4 A- 4 B  show an implementation of a device in which the access portion opening  180 , the penetrable barrier  140  and the retention structure  120  can be over-molded by the cover  110  such that the cover  110  can encapsulate and bond the access portion opening  180  and the upper surface of the penetrable barrier  140  positioned within the access portion opening  180 . The cover  110  can encapsulate and bond to at least an upper surface of the proximal retention structure  120  as well as the lower surface of the proximal retention structure  120  (see, for example,  FIG.  4 B ). The cover  110  can also encapsulate the flanged portion  122  such that the cover  110  bonds to at least the upper surface and also the lower surface of the flanged portion  122 . The penetrable barrier  140  can be exposed or accessible on a proximal end region. The cover  110  can extend across the entire proximal end region of the device  100  such that it bonds to the flanged portion  122  and to the proximal end region of the penetrable barrier  140  positioned therein. As such, the cover  110  can supplement the bond between the penetrable barrier  140  and the inner surfaces of the device near the access portion opening  180  such as within the flanged region  120  and the inner surfaces of the proximal end region of the housing  130 . The cover  110  can maintain or help to maintain a seal of the reservoir chamber volume. In some implementations, the cover  110  maintains the seal of the penetrable barrier  140  within the access portion opening  180  such that the seal of the reservoir chamber  160  need not rely on bonding between the surfaces of the housing  130  and the surfaces of the penetrable barrier  140 . In some implementations, the cover  110  eliminates any need for a bond between the housing  130  and the penetrable barrier  140 . Certain surface treatments can also be used during manufacturing of the devices described herein to enhance bonding between various components, including for example but not limited to, bonding primer agents such as NUSIL MED  161  or other surface activation techniques such as plasma treatment of the surfaces to be bonded. 
     The cover  110  and the proximal retention structure  120  (or any other region coupled to the cover  110  such as the flanged portion  122 ), can have corresponding shape profiles. The thickness of the over-molded cover  110  can vary from approximately 0.007″ to approximately 0.025″. The cover  110  can extend beyond the outer diameter of the flanged portion  122  as best shown in  FIGS.  4 A and  4 B . The cover  110  can also extend upward from the upper surface of the flanged portion  122  and provide a slightly thicker and slightly higher profile to the access portion under the conjunctiva. During injection of the therapeutic agent into the reservoir chamber  160 , the needle can extend through the cover  110  as it penetrates the barrier  140 . The cover  110 , like the penetrable barrier  140 , can be configured to re-seal when the needle or other sharp object is withdrawn. 
     The proximal retention structure  120  can include one or more through-holes, apertures, indentations or other features. Again with respect to  FIGS.  4 A- 4 B , the flanged portion  122  can include one or more apertures  125  extending therethrough. Upon application of the cover  110 , the apertures  125  can create mechanical struts of the over-molded cover material that extend through one or more regions of the flanged portion  122 . The mechanical struts of over-molded cover material can provide some anchoring support as well as facilitating good filling of the over-mold. The apertures  125  can also allow for a thin, uniform layer of over-mold material to form on the underside of the flanged portion  122  or other another region of the retention structure during over-molding. It should be appreciated, however, that mechanical struts of the over-molded material can be formed by over-molded material extending only partially through apertures in the flanged portion  122 . Further, instead of apertures  125 , the flanged portion  122  can include only partial-thickness holes or indentations in the flanged portion  122 . The indentations can be on an external surface of the flanged portion  122  such as in the upper and/or lower surfaces of the flanged portion  122 . The external surfaces of the flanged portion  122  can also be textured such that the over-molded material of the cover  110  can penetrate and fill additional indented regions of the flanged portion  122  to provide a better coupling between the flanged portion  122  and the material of the cover  110 . 
     The cover  110  can be an over-molded, high durometer material such as a translucent, liquid silicone rubber like MED-4880 or MED-4860 (NuSil Silicone Technology, Carpinteria, Calif.). The penetrable barrier  140  positioned within the proximal end region of the housing  130  can be a pre-molded soft, high strength material such as a liquid injection molding silicone elastomer such as MED-4810 (NuSil Silicone Technology, Carpinteria, Calif.). 
       FIG.  5    illustrates another implementation of a device that can include, alternatively or in combination with the cover  110 , an anchor  250  to secure the septum structure within the access portion of the housing  130 . The anchor  250  can provide further support to the penetrable barrier  140  as well as providing perimeter seal and added physical integrity useful during repeated penetration of the barrier  140  to refill the device. In some implementations, the anchor  250  can be an annular element encircling at least a portion of the penetrable barrier  140 . An inner surface of the anchor  250  can contact and encircle at least a portion of the outer surface of the penetrable barrier  140 . In some implementations, the anchor  250  encircles the upper region  144 , the middle region  141 , the distal region  142  or a combination of one or more of the upper, middle and distal regions of the penetrable barrier  140 . The upper region  144  of the penetrable barrier  140  can be beveled such that the outer diameter of the upper region  144  is larger than the outer diameter of the middle region  141  of the penetrable barrier  140 . Similarly, the shape of the inner surface of the anchor  250  can be beveled to match the shape of the outer surface of the penetrable barrier  140 . Similarly, the inner surface of the anchor  250  can be shaped to match the outer surface of the distal region  142  of the penetrable barrier  140 , which can be straight or flared or have one or more tabs or flanged regions as described above. Further, the outer surface of the anchor  250  can have a geometry that matches at least a portion of the geometry of the housing  130  at the access portion. For example, the outer surface of the  250  can engage with an undercut feature  252  in the proximal end of the housing  130 . It should be appreciated that the anchor  250  can be, but is not necessarily, annular or ring-shaped. The anchor  250  can be any of a variety of shapes and can include one or more features that can be bonded to at least a region of the penetrable barrier. The outer surface of the anchor  250  can have any of a variety of shapes, including, but not limited to the rounded shape as shown in  FIG.  5   , curvilinear such as oval, circular, or elliptical, as well as being angular in shape such as triangular, rectangular, or other number of angles. The anchor  250  can have sufficient physical robustness so as to translate to a secure mechanical interference with internal aspects of the rigid, body device in the area of the penetrable barrier. 
     The penetrable barrier  140  can be pre-molded with a soft, high strength material such as a liquid injection molding silicone elastomer such as MED-4810 (NuSil Silicone Technology, Carpinteria, Calif.). The anchor  250  can be formed of a higher durometer material such as a translucent, liquid silicone rubber like MED-4880 (NuSil Silicone Technology, Carpinteria, Calif.). The pre-mold penetrable barrier  140  can be bonded to the annular anchor  250  creating a single septum structure for insertion within the proximal end of the housing  130 . The pre-mold penetrable barrier  140  and anchor  250  can be bonded together within the housing  130  or can be bounded outside the device and loaded into positioned once a single septum structure is formed. The higher durometer of the anchor  250  can resist deformation and create a mechanical lock fixing the location of the septum in the housing  130 . The pre-mold penetrable barrier  140  can apply radial compression to the outer anchor  250  and housing  130  to maintain septum seal performance. The radial compression of the penetrable barrier  140  can encourage re-sealing after penetration following filling or re-filling of the reservoir chamber, for example re-sealing of a needle track upon removal of the needle. The radial compression of the penetrable barrier  140  can be provided by the pre-mold penetrable barrier  140  being larger in dimension relative to the access portion of the housing  130  in which it is positioned and the access portion of the housing  130  being formed of a more rigid material than the softer, pre-mold penetrable barrier  140 . 
       FIG.  6    illustrates an interrelated implementation of a device that can include, alternatively or in combination with the cover  110 , an anchor  250 . As described above, the anchor  250  can secure the septum structure within the access portion opening  180  of the housing  130 . The anchor  250  can provide further support to the penetrable barrier  140  as well as providing perimeter seal and added physical integrity. As with other implementations described herein, the anchor  250  can be an annular element encircling at least a portion of the penetrable barrier  140 . An inner surface of the anchor  250  can contact and encircle at least a portion of the outer surface of the penetrable barrier  140 . The inner surface of the anchor  250  can have a shape that corresponds to the outer surface of the penetrable barrier  140  and the outer surface of the anchor  250  can have a shape that corresponds to the inner surface of the access portion opening  180  of the housing  130 , for example such that it engages an undercut feature  252  in the proximal end of the housing  130 . The anchor  250  can be formed of a high durometer material to provide further support to the penetrable barrier  140  as well as providing perimeter seal and added physical integrity as described above. The penetrable barrier  140  can be a pre-molded, low durometer material also as described above. Further, the penetrable barrier  140  can be oversized such that the penetrable barrier  140  provides radial compression to the anchor  250  to provide improved needle track sealing as described above. 
     As described above, the penetrable barrier  140  can include a distal region  142  having a flared, flanged or otherwise enlarged diameter compared to the middle region  141  and/or upper region  144  of the penetrable barrier  140 . The enlarged distal region  142  can be positioned within the access portion opening  180 , for example, where the access portion opening  180  opens into the reservoir chamber  160  at a proximal end region of the reservoir chamber  160 . As shown in  FIG.  6   , the penetrable barrier  140  can also include a sealing element  254  near its distal end region that is flared and/or creates a “skirt” within a proximal end region of the reservoir chamber  160 . The sealing element  254  can be positioned in a proximal end of the reservoir chamber  160  of the housing  130  to provide a secondary seal and to prevent withdrawal of the penetrable barrier  140  in a proximal direction. It should be appreciated the sealing element  254  can be a separate element coupled to the penetrable barrier  140 , for example to the distal region  142  of the penetrable barrier  140 . Alternatively, the sealing element  254  can be integral with the penetrable barrier  140  such as the flared distal end region  142  shown in  FIG.  4 B . As such, the sealing element  254  can be a low durometer material that is the same as or different from the material of the penetrable barrier  140 . It should also be appreciated that the variations described above, such as the cover  110  can also be incorporated with the implementation shown in  FIG.  6   . It should be appreciated that the one or more of the components described herein can optionally be included in any feasible combination with the various implementations described herein. 
     The housing  130  can be machined from a piece of material, or injection molded, so as to form the retention structure  120 , flange  122  and/or the narrowed portion  121 . As described above, the penetrable barrier  140  can be pre-molded and the cover  110  can be over-molded. Alternatively, the cover  110  can be pre-molded and bonded to the pre-molded penetrable barrier  140 . The penetrable barrier  140  and cover  110  can be the same material and over-molded around the flange  122  using a single step injection molding process. Alternatively, the penetrable barrier  140  or cover  110  can be two different materials and over molded around the flange and cured in two independent steps. Further, the anchor  250  and/or sealing element  254  can be pre-molded and bonded to pre-molded penetrable barrier  140 . The anchor  250  and/or sealing element  254  can be casted in the housing and the pre-penetrable barrier  140  can be compressed into the housing and bonded to the anchor  250  and/or sealing element  254 . Alternatively, the sealing element  254  can be formed by a distal flared portion of the pre-molded penetrable barrier  140 . 
     Therapeutics 
     Initial filling of the device  100  with one or more therapeutic agents can occur prior to insertion or after insertion in a patient&#39;s eye. The penetrable barrier  140  as well as the cover  110 , if present, can be penetrated with a needle or access device attached to a syringe or injection device containing therapeutic agent. The cover  110  and the penetrable barrier  140  can be penetrated during filling and/or refilling of the reservoir chamber  160 . The needle or access device can be inserted through the penetrable barrier  140  until a distal opening of the needle enters the reservoir chamber  160 . The contents of the syringe or injection device can be injected into the reservoir chamber  160  and the needle or access device can be removed from the penetrable barrier  140 . The cover  110  and the penetrable barrier  140  can be configured to reseal after penetration during filling and/or refilling of the reservoir chamber  160 . The penetrable barrier  140  can reseal around the path created by the needle or access device upon its removal. The device  100  also can be periodically refilled with therapeutic agent following surgical placement as needed by accessing the implanted device  100  and without necessitating device removal. The conjunctiva  16  can be lifted or incised away. Alternatively, the conjunctiva can be pierced with the needle or access device used to fill the device  100  such that a single penetration is performed through each of the conjunctiva, cover  110  (if present), and penetrable barrier  140 . Once the needle or access device is inserted and located at the appropriate depth within the reservoir chamber  160 , injection of fresh therapeutic solution or exchange of pre-existing reservoir contents with fresh therapeutic solution can take place. 
     The therapeutic devices described herein can be implanted in the eye to treat the eye for as long as is helpful and beneficial to the patient. For example the device can be implanted for at least about 1 year, 2 years, 3 years, 4 year, 5 years and up to permanently for the life of the patient. Alternatively or in combination, the device can be removed when no longer helpful or beneficial for treatment of the patient. In other implementations, the device can be implanted for at least about 4 years to 10 years, for example a duration of treatment period for a chronic disease such as diabetic macular edema or age-related macular degeneration. The device can be periodically refilled in the physician&#39;s office with new therapeutic agent as indicated by disease progression. For diseases such as age-related macular degeneration, the device can be refilled as frequently as once every week, bi-weekly, monthly, bi-monthly, every 3 months, every 4 to 6 months, every 3 to 9 months, every 12 months, or any other period as indicated to treat a disease. 
     It should be appreciated that a variety of diseases and/or conditions can be treated with the devices and systems described herein, for example: glaucoma, macular degeneration, retinal disease, proliferative vitreoretinopathy, diabetic retinopathy, uveitis, keratitis, cytomegalovirus retinitis, cystoid macular edema, herpes simplex viral and adenoviral infections and other eye diseases, eye infections (including, but not limited to, infections of the skin, eyelids, conjunctivae, and/or lacrimal excretory system), orbital cellulitis, dacryoadenitis, hordeolum, blepharitis, conjunctivitis, keratitis, corneal infiltrates, ulcers, endophthalmitis, panophthalmitis, viral keratitis, fungal keratitis herpes zoster ophthalmicus, viral conjunctivitis, viral retinitis, uveitis, strabismus, retinal necrosis, retinal disease, vitreoretinopathy, diabetic retinopathy, cytomegalovirus retinitis, cystoids macular edema, herpes simplex viral and adenoviral injections, scleritis, mucormycosis, canaliculitis, acanthamoeba keratitis, toxoplasmosis, giardiasis, leishmanisis, malaria, helminth infection, etc. It also should be appreciated that medical conditions besides ocular conditions can be treated with the devices and systems described herein. For example, the devices can deliver drugs for the treatment of inflammation, infection, cancerous growth. It should also be appreciated that any number of drug combinations can be delivered using any of the devices and systems described herein. 
     The devices described herein can be used to deliver essentially any substance. As used herein, “substance,” “drug” or “therapeutic” is an agent or agents that ameliorate the symptoms of a disease or disorder or ameliorate the disease or disorder including, for example, small molecule drugs, proteins, nucleic acids, polysaccharides, and biologics or combination thereof. Therapeutic agent, therapeutic compound, therapeutic regimen, or chemotherapeutic include conventional drugs and drug therapies, including vaccines, which are known to those skilled in the art. Therapeutic agents include, but are not limited to, moieties that inhibit cell growth or promote cell death, that can be activated to inhibit cell growth or promote cell death, or that activate another agent to inhibit cell growth or promote cell death. Optionally, the therapeutic agent can exhibit or manifest additional properties, such as, properties that permit its use as an imaging agent, as described elsewhere herein. Exemplary therapeutic agents include, for example, cytokines, growth factors, proteins, peptides or peptidomimetics, bioactive agents, photosensitizing agents, radionuclides, toxins, anti-metabolites, signaling modulators, anti-cancer antibiotics, anti-cancer antibodies, angiogenesis inhibitors, radiation therapy, chemotherapeutic compounds or a combination thereof. The drug may be any agent capable of providing a therapeutic benefit. In an embodiment, the drug is a known drug, or drug combination, effective for treating diseases and disorders of the eye. In non-limiting, exemplary embodiments, the drug is an antiinfective agent (e.g., an antibiotic or antifungal agent), an anesthetic agent, an anti-VEGF agent, an anti-inflammatory agent, a biological agent (such as RNA), an intraocular pressure reducing agent (i.e., a glaucoma drug), or a combination thereof. Non-limiting examples of drugs are provided below. 
     The therapeutic agent can include a macromolecule, for example an antibody or antibody fragment. The therapeutic macromolecule can include a VEGF inhibitor, for example commercially available Lucentis™. The VEGF (Vascular Endothelial Growth Factor) inhibitor can cause regression of the abnormal blood vessels and improvement of vision when released into the vitreous humor of the eye. Examples of VEGF inhibitors include Lucentis™ Avastin™, Macugen™ and VEGF Trap. The therapeutic agent can include small molecules such as of a corticosteroid and analogues thereof. For example, the therapeutic corticosteroid can include one or more of trimacinalone, trimacinalone acetonide, dexamethasone, dexamethasone acetate, fluocinolone, fluocinolone acetate, or analogues thereof. Alternatively or in combination, the small molecules of therapeutic agent can include a tyrosine kinase inhibitor comprising one or more of axitinib, bosutinib, cediranib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, lestaurtinib, nilotinib, semaxanib, sunitinib, toceranib, vandetanib, or vatalanib, for example. The therapeutic agent can include an anti-VEGF therapeutic agent. Anti-VEGF therapies and agents can be used in the treatment of certain cancers and in age-related macular degeneration. Examples of anti-VEGF therapeutic agents suitable for use in accordance with the embodiments described herein include one or more of monoclonal antibodies such as bevacizumab (Avastin™) or antibody derivatives such as ranibizumab (Lucentis™), or small molecules that inhibit the tyrosine kinases stimulated by VEGF such as lapatinib (Tykerb™), sunitinib (Sutent™), sorafenib (Nexavar™) axitinib, or pazopanib. The therapeutic agent can include a therapeutic agent suitable for treatment of dry AMD such as one or more of Sirolimus™ (Rapamycin), Copaxone™ (Glatiramer Acetate), Othera™, Complement C5aR blocker, Ciliary Neurotrophic Factor, Fenretinide or Rheopheresis. The therapeutic agent can include a therapeutic agent suitable for treatment of wet AMD such as one or more of REDD14NP (Quark), Sirolimus™ (Rapamycin), ATG003; Regeneron™ (VEGF Trap) or complement inhibitor (POT-4). The therapeutic agent can include a kinase inhibitor such as one or more of bevacizumab (monoclonal antibody), BIBW 2992 (small molecule targeting EGFR/Erb2), cetuximab (monoclonal antibody), imatinib (small molecule), trastuzumab (monoclonal antibody), gefitinib (small molecule), ranibizumab (monoclonal antibody), pegaptanib (small molecule), sorafenib (small molecule), dasatinib (small molecule), sunitinib (small molecule), erlotinib (small molecule), nilotinib (small molecule), lapatinib (small molecule), panitumumab (monoclonal antibody), vandetanib (small molecule) or E7080 (targeting VEGFR2NEGFR2, small molecule commercially available from Esai, Co.) 
     A variety of therapeutic agents can be delivered using the drug delivery implants described herein, including: anesthetics, analgesics, cell transport/mobility impending agents such as colchicine, vincristine, cytochalasin B and related compounds; antiglaucoma drugs including beta-blockers such as timolol, betaxolol, atenolol, and prostaglandins, lipid-receptor agonists or prostaglandin analogues such as bimatoprost, travoprost, latanoprost, unoprostone etc; alpha-adrenergic agonists, brimonidine or dipivefrine, carbonic anhydrase inhibitors such as acetazolamide, methazolamide, dichlorphenamide, diamox; and neuroprotectants such as nimodipine and related compounds. 
     Additional examples include antibiotics such as tetracycline, chlortetracycline, bacitracin, neomycin, polymyxin, gramicidin, oxytetracycline, chloramphenicol, gentamycin, and erythromycin; antibacterials such as sulfonamides, sulfacetamide, sulfamethizole and sulfisoxazole; anti-fungal agents such as fluconazole, nitrofurazone, amphotericin B, ketoconazole, and related compounds; anti-viral agents such as trifluorothymidine, acyclovir, ganciclovir, DDI, AZT, foscamet, vidarabine, trifluorouridine, idoxuridine, ribavirin, protease inhibitors and anti-cytomegalovirus agents; antiallergenics such as methapyriline; chlorpheniramine, pyrilamine and prophenpyridamine; anti-inflammatories such as hydrocortisone, dexamethasone, fluocinolone, prednisone, prednisolone, methylprednisolone, fluorometholone, betamethasone and triamcinolone; decongestants such as phenylephrine, naphazoline, and tetrahydrazoline; miotics, muscarinics and anti-cholinesterases such as pilocarpine, carbachol, di-isopropyl fluorophosphate, phospholine iodine, and demecarium bromide; mydriatics such as atropine sulfate, cyclopentolate, homatropine, scopolamine, tropicamide, eucatropine; sympathomimetics such as epinephrine and vasoconstrictors and vasodilators; Ranibizumab, Bevacizamab, and Triamcinolone. 
     Antiinflammatories, such as non-steroidal anti-inflammatories (NSAIDs) may also be delivered, such as cyclooxygenase-1 (COX-1) inhibitors (e.g., acetylsalicylic acid, for example ASPIRIN from Bayer AG, Leverkusen, Germany; ibuprofen, for example ADVIL from Wyeth, Collegeville, Pa.; indomethacin; mefenamic acid), COX-2 inhibitors (CELEBREX from Pharmacia Corp., Peapack, N.J.; COX-1 inhibitors), including a prodrug NEPAFENAC; immunosuppressive agents, for example Sirolimus (RAPAMUNE, from Wyeth, Collegeville, Pa.), or matrix metalloproteinase (MMP) inhibitors (e.g., tetracycline and tetracycline derivatives) that act early within the pathways of an inflammatory response. Anticlotting agents such as heparin, antifibrinogen, fibrinolysin, anti clotting activase, etc., can also be delivered. 
     Antidiabetic agents that may be delivered using the disclosed implants include acetohexamide, chlorpropamide, glipizide, glyburide, tolazamide, tolbutamide, insulin, aldose reductase inhibitors, etc. Some examples of anti-cancer agents include 5-fluorouracil, adriamycin, asparaginase, azacitidine, azathioprine, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, cyclophosphamide, cyclosporine, cytarabine, dacarbazine, dactinomycin, daunorubicin, doxorubicin, estramustine, etoposide, etretinate, filgrastin, floxuridine, fludarabine, fluorouracil, fluoxymesterone, flutamide, goserelin, hydroxyurea, ifosfamide, leuprolide, levamisole, lomustine, nitrogen mustard, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, pentostatin, pipobroman, plicamycin, procarbazine, sargramostin, streptozocin, tamoxifen, taxol, teniposide, thioguanine, uracil mustard, vinblastine, vincristine and vindesine. 
     Hormones, peptides, steroids, nucleic acids, saccharides, lipids, glycolipids, glycoproteins, and other macromolecules can be delivered using the present implants. Examples include: endocrine hormones such as pituitary, insulin, insulin-related growth factor, thyroid, growth hormones; heat shock proteins; immunological response modifiers such as muramyl dipeptide, cyclosporins, interferons (including α, β, and γ interferons), interleukin-2, cytokines, FK506 (an epoxy-pyrido-oxaazcyclotricosine-tetrone, also known as Tacrolimus), tumor necrosis factor, pentostatin, thymopentin, transforming factor beta2, erythropoetin; antineogenesis proteins (e.g., anti-VEGF, Interferons), among others and anticlotting agents including anticlotting activase. Further examples of macromolecules that can be delivered include monoclonal antibodies, brain nerve growth factor (BNGF), ciliary nerve growth factor (CNGF), vascular endothelial growth factor (VEGF), and monoclonal antibodies directed against such growth factors. Additional examples of immunomodulators include tumor necrosis factor inhibitors such as thalidomide. 
     In addition, nucleic acids can also be delivered wherein the nucleic acid may be expressed to produce a protein that may have a variety of pharmacological, physiological or immunological activities. Thus, the above list of drugs is not meant to be exhaustive. A wide variety of drugs or agents may be used in the present invention, without restriction on molecular weight, etc. 
     Other agents include anti-coagulant, an anti-proliferative, imidazole antiproliferative agent, a quinoxaline, a phsophonylmethoxyalkyl nucleotide analog, a potassium channel blocker, and/or a synthetic oligonucleotide, 5-[1-hydroxy-2-[2-(2-methoxyphenoxyl) ethylamino] ethyl]-2-methylbenzenesulfonamide, a guanylate cyclase inhibitor, such as methylene blue, butylated hydroxyanisole, and/or N-methylhydroxylamine, 2-(4-methylaminobutoxy) diphenylmethane, apraclonidine, a cloprostenol analog or a fluprostenol analog, a crosslinked carboxy-containing polymer, a sugar, and water, a non-corneotoxic serine-threonine kinase inhibitor, a nonsteroidal glucocorticoid antagonist, miotics (e.g., pilocarpine, carbachol, and acetylcholinesterase inhibitors), sympathomimetics (e.g., epinephrine and dipivalylepinephxine), beta-blockers (e.g., betaxolol, levobunolol and timolol), carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide and ethoxzolamide), and prostaglandins (e.g., metabolite derivatives of arachidonic acid, or any combination thereof. 
     Additional examples of beneficial drugs that may be employed and the specific conditions to be treated or prevented are disclosed in Remington, supra; The Pharmacological Basis of Therapeutics, by Goodman and Gilman, 19th edition, published by the MacMillan Company, London; and The Merck Index, 13th Edition, 1998, published by Merck &amp; Co., Rahway, N.J., which is incorporated herein by reference. 
     While this specification contains many specifics, these should not be construed as limitations on the scope of what is claimed or of what may be claimed, but rather as descriptions of features specific to particular embodiments. Certain features that are described in this specification in the context of separate embodiments can also be implemented in combination in a single embodiment. Conversely, various features that are described in the context of a single embodiment can also be implemented in multiple embodiments separately or in any suitable sub-combination. Moreover, although features may be described above as acting in certain combinations and even initially claimed as such, one or more features from a claimed combination can in some cases be excised from the combination, and the claimed combination may be directed to a sub-combination or a variation of a sub-combination. Similarly, while operations are depicted in the drawings in a particular order, this should not be understood as requiring that such operations be performed in the particular order shown or in sequential order, or that all illustrated operations be performed, to achieve desirable results. Only a few examples and implementations are disclosed. Variations, modifications and enhancements to the described examples and implementations and other implementations may be made based on what is disclosed. 
     In the descriptions above and in the claims, phrases such as “at least one of” or “one or more of” may occur followed by a conjunctive list of elements or features. The term “and/or” may also occur in a list of two or more elements or features. Unless otherwise implicitly or explicitly contradicted by the context in which it is used, such a phrase is intended to mean any of the listed elements or features individually or any of the recited elements or features in combination with any of the other recited elements or features. For example, the phrases “at least one of A and B;” “one or more of A and B;” and “A and/or B” are each intended to mean “A alone, B alone, or A and B together.” A similar interpretation is also intended for lists including three or more items. For example, the phrases “at least one of A, B, and C;” “one or more of A, B, and C;” and “A, B, and/or C” are each intended to mean “A alone, B alone, C alone, A and B together, A and C together, B and C together, or A and B and C together.” 
     Use of the term “based on,” above and in the claims is intended to mean, “based at least in part on,” such that an unrecited feature or element is also permissible.