the eye is a model organ for the implantation of devices that provide long - lasting infusion of a therapeutic agent . it is easily accessible for implantation of such a device and success of therapy is measurable objectively by direct visualization of the intraocular structures and by patient responsiveness . the treatment of posterior uveitis and vitreous inflammation usually involves a chronic course of therapy often over a period of years . sub - tenon 's and intravitreal steroid injections also can require frequent retreatment to adequately control disease . treatment with powerful systemic corticosteroid and immunomodulatory agents most often have poor vitreous penetration and can be associated with severe systemic side effects . implantable devices offer an alternative therapeutic approach that can circumvent many challenges of these other modes of therapy . vitrasert , a nonbiodegradable implant , delivers ganciclovir into the eye for the treatment of acquired - immunodeficiency - syndrome ( aids)-related cytomegalovirus ( cmv ) . more recently , there are serious investigations of biodegradable polymers that encapsulate particulate systems for long - lasting delivery of therapeutic nanoparticles which can be injected intravitreally . in this review , nonbiodegradable devices require surgical implantation and contain a drug reservoir within a permeable polymer membrane . although useful in some clinical settings , nonbiodegradable implants are not without limitations . due to their large size a relatively large incision furthermore , these devices typically require removal and reimplantation of a second device once the drug has been completely released . the rate of drug release can be slowed by decreasing the surface area or increasing the thickness of the permeable membrane . complications associated with these devices include retinal detachment , vitreous hemorrhage , epiretinal membrane formation , and dissolution of the implant . these devices are made of polyvinyl alcohol ( pva ) , a permeable polymer functioning as a structural component , and ethylene vinyl acetate ( eva ) , a nonpermeable hydrophobic polymer used to restrict drug release . these devices are essentially inert , almost devoid of intraocular inflammatory response when implanted , but must be removed to prevent fibrous encapsulation after drug delivery is complete . the initial device of this type was originally formulated to contain 5-fluorouracil and placed subconjuctivally to prevent scarring following glaucoma filtration . subsequent devices have been used for intravitreal dexamethasone and cyclosporine implantation [ 6 , 7 ] . the major clinical application of this device type was the ganciclovir ( vitrasert , bausch and lomb ) implant , which was used frequently prior to the development of highly active antiretroviral therapy for hiv . these devices are water impermeable and contain deep macrovoids which increase the surface area for drug release . polysulfone capillary fiber implants have only been used experimentally for carboxyfluorescein dye release and daunomycin in rabbit eyes [ 8 , 9 ] . biodegradable devices are particularly useful as intraocular implants since they do not need to be removed and have increased flexibility in their shape . polylactic acid ( pla ) , polyglycolic acid ( pga ) , and polylactic - co - glycolic acid ( plga ) are the most studied synthetic biodegradable polymers . these polymers are widely used as suture materials , bone screws and pins , vascular grafts and stents , and surgical scaffolds for tissue regeneration . pga is a semicrystalline polymer that is synthesized using toxic solvents limiting its potential for clinical use since any residual solvent may react with the drug or tissue . plga is a copolymer of pla and pga and is the most widely used biodegradable polymer for drug delivery . the ratio of pla to pga can be adjusted to modulate the rate of polymer degradation . the rate of drug release depends on the total surface area of the device , the percentage of loaded drug , the water solubility of the drug , and the speed of polymer degradation for human immunodeficiency virus . initial burst from the surface of the implant.diffusion phase during biodegradation of the polymer.final burst from the disintegration of the implant . the initial burst is followed by a longer steady drug release and is well suited for diseases that require an initial loading dose followed by tapering . however , the first and last phases release higher drug concentrations and potential toxic effects at these levels need to be considered . blending polymers with different molecular weights can reduce the final drug burst and result in a more stable agent release [ 13 , 14 ] . examples of plga devices include dexamethasone ( ozurdex ) and indomethacin . polycaprolactone ( pcl ) is a polymer of -caprolactone , a semi - crystalline and hydrophobic compound that is biodegradable and biocompatible . it is widely used in the biomedical industry ( e.g. , monocryl suture , artificial skin , and osteosynthetic material ) . it is very slowly degraded in the human body by hydrolysis of its ester linkages and its fragments are phagocytized . when the implants are immersed in water , there is dissolution leaving pores in the pcl , allowing for a long - term , well - controlled steady release rate over a period of greater than one year [ 16 , 17 ] . intravitreally - placed pcl devices containing dexamethasone delivers the drug in a controlled and prolonged manner for at least 55 weeks . at 55 weeks it was found to be very well tolerated in rabbit eyes with no sign of anterior or posterior segment inflammation . pcl devices containing triamcinolone acetate have also been implanted in the subretinal space of rabbit eyes and was found to be well- tolerated by retinal tissue , releasing the drug for at least 4 weeks without an inflammatory response . pcl can also be mixed with other polymers , usually more hydrophilic than pcl , to form copolymers which degrade at faster rates . these have been used experimentally for drug delivery of cyclosporine and tacrolimus [ 21 , 22 ] . polyanhydrides are a class of biodegradable polymers that degrade by surface erosion into biocompatible monomers that are then metabolized and removed from the body . surface erosion provides a more controlled drug release compared to drugs that are released by bulk erosion , making them useful as drug delivery devices . aliphatic polyanhydrides degrade in a few days while some aromatic polyanhydrides degrade over few years . degradation rates of copolymers of aliphatic and aromatic polyanhydrides vary between these extremes and this feature of polyanhydrides gives an opportunity for making a drug delivery system which can provide the release of drugs for a desired time length of treatment . the most frequently used is a copolymer of the 1,3-bis(carboxyphenoxypropane ) ( pcpp ) and sebacic acid ( sa ) . pcpp is aromatic and hydrophobic and by itself has a long lifetime of over 3 years , while sa is aliphatic and hydrophilic with a lifetime of a few days . the 80  :  20 copolymer has been fda approved for intracranial delivery of carmustine ( gliadel ) for treatment of brain tumors , and intravenous delivery for treatment of recurrent hodgkin 's lymphoma and multiple myeloma . in ocular use they have been investigated in the delivery of 5-fluorouracil , taxol , and etoposide for experimental glaucoma filtration surgery in a non - human primate model [ 26 , 27 ] . vitrasert ( bausch & lomb , rochester , ny ) is a pva - eva reservoir implant consisting of a pellet containing at least 4.5  mg of ganciclovir as the active ingredient and 0.25% magnesium stearate as the inactive ingredient with a ganciclovir release rate of 1  mcg / hour ( figure 1(a ) ) . a 5 - 6  mm scleral incision is made at pars plana and after trimming away any prolapsed vitreous , the device is implanted into the vitreous cavity . it is sutured in place on the sclera prior to closing the sclera and overlying conjunctiva . it is removed if another ganciclovir implant is placed ( usually after 6 months ) or if there are any complications such as endophthalmitis or retinal detachment . the vitrasert disc is composed of outer and inner permeable pva layers surrounding a discontinuous hydrophobic eva film . the device allows diffusion of fluid into the device dissolving the drug pellet , which then diffuses into the vitreous at a constant rate . retisert ( bausch & lomb , rochester , ny ) is a tablet containing 0.59  mg of fluocinolone acetonide that is coated with nonbiodegradable pva and silicon laminate ( figure 1(b ) ) . it is 5  mm long , 2  mm wide and 1.5  mm thick with a release rate of 0.30.6  mcg / d over a period of 30 months . it is inserted into the vitreous cavity and sutured to the sclera through a pars plana surgical technique similar to vitrasert . in april 2005 it became the first fda - approved device for use in the treatment of chronic noninfectious posterior uveitis . in clinical studies retisert was found to significantly reduce inflammation and lower intravitreal vascular endothelial growth factor ( vegf ) levels . in patients with noninfectious posterior uveitis treated with retisert , the recurrence rate of uveitis was reduced from 62% before treatment to 4% , 10% , and 20% at 1 , 2 , and 3 years , respectively following treatment [ 30 , 31 ] . despite the excellent reduction of uveitis , at 34 weeks , 51% of patients had an increased intraocular pressure ( iop ) that required pressure lowering agents . at 3 years in addition , 100% of phakic patients developed cataract formation within 3 years of implantation . other side effects included hypotony ( 6.1% ) , retinal detachment ( 2.9% ) , endophthalmitis ( 0.4% ) , and the need for explantation at 2 years ( 3.6% ) [ 31 , 32 ] . recently , the multicenter uveitis steroid treatment ( must ) trial compared the relative effectiveness of systemic therapy and fluocinolone acetonide implant for the treatment of noninfectious uveitis in 479 eyes over 2 years . it found that both treatment groups were effective and neither group was superior to the other in improving visual acuity . systemic therapy was well tolerated while the implant group had an 80% risk of cataract surgery and 61% required treatment for elevated intraocular pressures . watertown , ma ) is an injectable nonbiodegradable intravitreal implant containing fluocinolone acetonide ( figure 1(c ) ) . it is 3.5  mm long and 0.37  mm wide and releases fluocinolone acetonide at a rate of 0.2  mcg or 0.5  mcg per day over 1836 months . the fluocinolone acetonide for diabetic macular edema ( fame ) study group tested the low dose 0.2  mcg insert and the high dose 0.5  mcg insert against a sham implant . at 24 months , 28% of those receiving either dose had an improvement of 15 in best - corrected visual acuity ( bcva ) letters compared to 16% of those in the control . at 36 months , it was 33.0% in the low dose and 31.9% in the high dose compared with 21.4% in the sham . increased incidence of cataracts was seen in implanted eyes but long - term vision was not compromised . increase in intraocular pressure was also a concern with implantation of the device . at 36 months , 4.8% of those receiving the low dose implant required glaucoma surgery but visual outcome in addition to its use in dme patients , phase ii trials for the treatment of exudative age - related macular degeneration ( amd ) and retinal vein occlusion are also being conducted . ( 1 ) i - vation ( surmodics , eden prairie , mn ) is a 0.4  mm  0.21  mm titanium helical nonbiodegradable implant that contains 0.925  mcg triamcinolone acetonide ( figure 1(d ) ) . the helical design increases the surface area for drug release and stabilizes the device onto the sclera . it was recently found to be effective in the treatment of diabetic macular edema after 24 months in a phase i clinical trial although all phakic patients developed visually significant cataracts and increases in intraocular pressure occurred in 50% of eyes . ( surmodics , eden prairie , mn ) is a 0.4  mm  0.21  mm titanium helical nonbiodegradable implant that contains 0.925  mcg triamcinolone acetonide ( figure 1(d ) ) . the helical design increases the surface area for drug release and stabilizes the device onto the sclera . it was recently found to be effective in the treatment of diabetic macular edema after 24 months in a phase i clinical trial although all phakic patients developed visually significant cataracts and increases in intraocular pressure occurred in 50% of eyes . ( 2 ) verisome verisome ( ramscor , inc . , menlo park , ca ) is a nonpolymer - based intraocular drug delivery system that provides long - acting intravitreal drug therapy . triamcinolone has been used investigationally providing a mean vitreous level of 1.1  mcg / ml for up to 1 year . menlo park , ca ) is a nonpolymer - based intraocular drug delivery system that provides long - acting intravitreal drug therapy . triamcinolone has been used investigationally providing a mean vitreous level of 1.1  mcg / ml for up to 1 year . , irvine ca ) is a rod - shaped 6.5  0.45  mm pellet composed of a mixture of dexamethasone as the active pharmaceutical ingredient ( api ) and biodegradable plga ( figure 1(e ) ) . although dexamethasone has a short half - life relative to triamcinolone , it is 20 and 5 times more potent than fluocinolone and triamcinolone , respectively ( table 3 ) .ozurdex is placed intravitreally through the pars plana with an injector using a 22-gauge needle device . the insert contains 0.7  mg dexamethasone and provides peak doses for 2 months initially followed by lower doses for up to 6 months . ozurdex received fda approval in june 2009 for the treatment of macular edema associated with retinal vein occlusion , and in september 2010 , it became the second fda - approved therapeutic agent for the treatment of noninfectious posterior uveitis.in a 26-week , multicenter , double - masked , randomized clinical study in which 229 patients were randomized in a 1  :  1  :  1 ratio receiving 0.70  mg ozurdex ( n = 77 ) , 0.35  mg ozurdex ( n = 76 ) , or sham injection ( n = 76 ) . eighty - one percent of patients had intermediate uveitis . at the eighth week primary endpoint , 47% , 36% and 12% of patients had no vitreous inflammation . in addition , both treatment groups achieved a 3-line improvement in visual acuity and reduced central macular thicknesses on ocular coherence tomography at 8 weeks that was statistically significant compared to the sham group . twenty - three percent of eyes in the 0.7  mg ozurdex group required iop - lowering agents and none needed surgical intervention for glaucoma . cataract formation was seen in 15% in the 0.7  mg group , 12% in the 0.34  mg group , and 7% in the sham group [ 39 , 40 ] . , irvine ca ) is a rod - shaped 6.5  0.45  mm pellet composed of a mixture of dexamethasone as the active pharmaceutical ingredient ( api ) and biodegradable plga ( figure 1(e ) ) . although dexamethasone has a short half - life relative to triamcinolone , it is 20 and 5 times more potent than fluocinolone and triamcinolone , respectively ( table 3 ) . ozurdex is placed intravitreally through the pars plana with an injector using a 22-gauge needle device . the insert contains 0.7  mg dexamethasone and provides peak doses for 2 months initially followed by lower doses for up to 6 months . ozurdex received fda approval in june 2009 for the treatment of macular edema associated with retinal vein occlusion , and in september 2010 , it became the second fda - approved therapeutic agent for the treatment of noninfectious posterior uveitis . in a 26-week , multicenter , double - masked , randomized clinical study in which 229 patients were randomized in a 1  :  1  :  1 ratio receiving 0.70  mg ozurdex ( n = 77 ) , 0.35  mg ozurdex ( n = 76 ) , or sham injection ( n = 76 ) . in addition , both treatment groups achieved a 3-line improvement in visual acuity and reduced central macular thicknesses on ocular coherence tomography at 8 weeks that was statistically significant compared to the sham group . twenty - three percent of eyes in the 0.7  mg ozurdex group required iop - lowering agents and none needed surgical intervention for glaucoma . cataract formation was seen in 15% in the 0.7  mg group , 12% in the 0.34  mg group , and 7% in the sham group [ 39 , 40 ] . ( 2 ) surodex surodex ( oculex pharmaceuticals , sunnyvale , ca ) is a 1.0  0.4  mm plga pellet that provides sustained release of dexamethasone after insertion into the anterior chamber . it is primarily targeted to reduce post - cataract surgery inflammation for 710 days . surodex ( oculex pharmaceuticals , sunnyvale , ca ) is a 1.0  0.4  mm plga pellet that provides sustained release of dexamethasone after insertion into the anterior chamber . cyclosporine a placed in the deep sclera adjacent to the suprachoroidal space has been found to be effective in controlling uveitis in an equine recurrent uveitis model . in a chronic uveitis rabbit model , 2  mg cyclosporine a conjugated to a pcl / plga copolymer was found to be significantly more effective than oral cyclosporine . plga discs containing 7  mg of indomethacin released over 3 weeks was evaluated in a rabbit model . although postoperative inflammation was decreased there was no significant decrease in posterior capsular opacification of the lens . the long - term drug delivery of small scale biodegradable devices has been recently investigated in experimental studies . ( 1 ) liposomesliposomes are spherical liposomal structures , about 0.01 to 10  m in diameter ( figure 2 ) . they are formed of a vesicular lipid bilayer separated by water or an aqueous buffer compartment . since the phospholipid bilayers are naturally occurring , they are biocompatible and minimize toxicity and immunogenicity.liposomes are colloidal particles made of phospholipids that encapsulate hydrophobic or hydrophilic therapeutic agents . they often contain inner aqueous spaces where hydrophilic enzymes remain soluble and hydrophobic outer layers that allow passage through natural membrane barriers.currently verteporfin ( visudyne , qlt inc . vancouver bc , canada ) is the only liposomal drug that is fda approved for use in the eye for the treatment of predominantly classic wet amd . liposomal amphoterecin b ( ambisome , gilead sciences , foster city , ca ) is used off - label for the treatment of fungal endophthalmitis and has been found to exhibit fewer side effects than the nonliposomal forms allowing for higher dosages ( up to 30 micrograms ) to be injected intravitreally . liposomes are spherical liposomal structures , about 0.01 to 10  m in diameter ( figure 2 ) . they are formed of a vesicular lipid bilayer separated by water or an aqueous buffer compartment . they can circumvent cell membrane barriers and protect drugs from metabolic or immune attack . since the phospholipid they often contain inner aqueous spaces where hydrophilic enzymes remain soluble and hydrophobic outer layers that allow passage through natural membrane barriers . vancouver bc , canada ) is the only liposomal drug that is fda approved for use in the eye for the treatment of predominantly classic wet amd . liposomal amphoterecin b ( ambisome , gilead sciences , foster city , ca ) is used off - label for the treatment of fungal endophthalmitis and has been found to exhibit fewer side effects than the nonliposomal forms allowing for higher dosages ( up to 30 micrograms ) to be injected intravitreally . ( 2 ) particulate ocular drug delivery systemsparticulate ocular drug delivery systems include nanoparticles and microparticles . although the distinction is often not consistent , nanoparticles are considered to be between 10 and 1,000  nm in size and microparticles 1 to 1,000  m in diameter . nanoparticles and microparticles are subdivided into nanospheres and microspheres which are a polymer - drug combinations where the drug is homogenously dispersed in the polymeric matrix , and nanocapsules / microcapsules , in which the drug particles or droplets are entrapped in a polymeric membrane ( figure 3 ) . although the distinction is often not consistent , nanoparticles are considered to be between 10 and 1,000  nm in size and microparticles 1 to 1,000  m in diameter . nanoparticles and microparticles are subdivided into nanospheres and microspheres which are a polymer - drug combinations where the drug is homogenously dispersed in the polymeric matrix , and nanocapsules / microcapsules , in which the drug particles or droplets are entrapped in a polymeric membrane ( figure 3 ) . ( 3 ) microparticlesmicroparticles are similar to liposomes in shape , size , and route of administration . however , nanoparticles offer several advantages over microsomes such as higher stability and larger drug - loading capabilities . surface polymer modifications also provide greater protection of the drug against degradation and phagocytosis by macrophages . although there are no currently used fda approved microparticle devices , a wide variety of therapeutic agents are being investigated to improve the cellular penetration and allow long - term delivery using microsphere and nanosphere technology ( table 4 ) . however , nanoparticles offer several advantages over microsomes such as higher stability and larger drug - loading capabilities . surface polymer modifications also provide greater protection of the drug against degradation and phagocytosis by macrophages . although there are no currently used fda approved microparticle devices , a wide variety of therapeutic agents are being investigated to improve the cellular penetration and allow long - term delivery using microsphere and nanosphere technology ( table 4 ) . ( 4 ) microspheresmicrospheres have been developed for sustained ocular delivery of therapeutic agents such as progesterone , adriamycin , and pegaptanib [ 4850 ] . microspheres composed of chitosan , a natural biodegradable polymer , have been used for transcorneal acyclovir delivery . a sustained release of microsphere - encapsulated cyclosporine was found to be present compared to cyclosporine solution . microspheres have been developed for sustained ocular delivery of therapeutic agents such as progesterone , adriamycin , and pegaptanib [ 4850 ] . microspheres composed of chitosan , a natural biodegradable polymer , have been used for transcorneal acyclovir delivery . a sustained release of microsphere - encapsulated cyclosporine was found to be present compared to cyclosporine solution . tamoxifen ( peg coated ) was found to be effective in the treatment of experimental autoimmune uveitis in a rat model . intravitreally injected nanoparticles containing ganciclovir and acyclovir have been studied in a rabbit model with steady drug concentrations , but were found to be associated with cataract formation and flare . scleral injections of pigment epithelium - derived factor ( pedf ) resulted in increased pedf expression in the retina and retinal pigment epithelium and resulted in significant reductions of choroidal neovascularization in mouse and pig models [ 55 , 56 ] . in a phase i clinical trial , recombinant adeno - associated viral mediated expression of ( raav - pedf ) was administered intravitreally in patients with exudative amd . although this resulted in transient intraocular inflammation ( 25% ) and iop elevations ( 21% ) , no other adverse events were seen and the majority of the patients achieved stable or improved visual acuity . tamoxifen ( peg coated ) was found to be effective in the treatment of experimental autoimmune uveitis in a rat model . intravitreally injected nanoparticles containing ganciclovir and acyclovir have been studied in a rabbit model with steady drug concentrations , but were found to be associated with cataract formation and flare . scleral injections of pigment epithelium - derived factor ( pedf ) resulted in increased pedf expression in the retina and retinal pigment epithelium and resulted in significant reductions of choroidal neovascularization in mouse and pig models [ 55 , 56 ] . in a phase i clinical trial , recombinant adeno - associated viral mediated expression of ( raav - pedf ) was administered intravitreally in patients with exudative amd . although this resulted in transient intraocular inflammation ( 25% ) and iop elevations ( 21% ) , no other adverse events were seen and the majority of the patients achieved stable or improved visual acuity . in conclusion , the eye is well suited for local delivery of therapeutics to treat vitreous inflammation as well as other pathologic conditions that induce visual loss . however , there are some unique challenges in designing local ocular drug delivery devices , which include implants , polymers , and micro- and nanoparticles . an integrated approach involving biomedical engineering , molecular biology , immunology , pathology , and pharmacology will continue to be critical to designing optimal devices for ocular inflammation and other diseases .
the eye is a well - suited organ for local delivery of therapeutics to treat vitreous inflammation as well as other pathologic conditions that induce visual loss . 
 several conditions are particularly challenging to treat and often require chronic courses of therapy . 
 the use of implantable intravitreal devices for drug delivery is an emerging field in the treatment of vitreous inflammation as well as other ophthalmologic diseases . 
 there are unique challenges in the design of these devices which include implants , polymers , and micro- and nanoparticles . 
 this paper reviews current and investigational drug delivery systems for treating vitreous inflammation as well as other pathologic conditions that induce visual loss . 
 the use of nonbiodegradable devices such as polyvinyl alcohol - ethylene vinyl acetate polymers and polysulfone capillary fibers , and biodegradable devices such as polylactic acid , polyglycolic acid , and polylactic - co - glycolic acid , polycaprolactones , and polyanhydrides are reviewed . 
 clinically used implantable devices for therapeutic agents including ganciclovir , fluocinolone acetonide , triamcinolone acetonide , and dexamethasone are described . finally , recently developed investigational particulate drug delivery systems in the form of liposomes , microspheres , and nanoparticles are examined .