posterior subtenon or intravitreal injection of immunomodulators and steroids is short lasting , requiring frequent administration . penetration of the posterior segment with topical and systemic agents can also prove challenging and can be associated with significant side effects . with these limitations , efforts are being made to develop and implement implantable devices that slowly release drug into the vitreous . the anatomy of the eye makes it an excellent organ for such a drug delivery system . this review describes current and investigational intravitreal drug delivery devices with a primary focus on their use in vitreous inflammation . studies in other eye diseases such as macular edema , infection , and neovascularization are also included to illustrate the versatility of these devices and technologies and their potential application to vitreous inflammation . the nonbiodegradable devices are implanted into the vitreous surgically due to their large size , with the exception of iluvien ( alimera sciences inc . , alpharetta , ga ; psivida inc . , watertown , ma ) which is smaller than the others . they usually require removal and reimplantation of a new device following depletion of the drug . these devices are made of a permeable membrane and include a drug - containing reservoir . the first implantable device for clinical use in the eye was composed of a nonbiodegradable polymer containing ganciclovir . this drug delivery system , vitrasert ( bausch & lomb , rochester , ny ) , was released to the market in 1996 for the treatment of acquired immunodeficiency syndrome- ( aids- ) related cytomegalovirus ( cmv ) retinitis [ 5 , 6 ] . also on the market iluvien , i - vation ( surmodics , eden prairie , mn ) , and the ranibizumab ( genentech , san francisco , ca ) port delivery system are still in the clinical trial phases for approval in the united states . vitrasert is a ganciclovir pellet coated in polyvinyl alcohol ( pva ) , a permeable polymer that allows drug diffusion , and ethylene vinyl acetate ( eva ) , an impermeable , a hydrophobic polymer that restricts release . it contains at least 4.5  mg of ganciclovir and 0.25% magnesium stearate as an inactive ingredient . the device is composed of outer and inner permeable pva layers sandwiching a discontinuous layer of impermeable eva . this combination of polymers results in a ganciclovir release rate of 1  mcg / hour that lasts 5 to 8 months before reimplantation is necessary . vitrasert has shown to be effective in treating cmv retinitis in aids patients , increasing median time to progression when compared to groups receiving intravenous ganciclovir . more recent studies suggest that , in the era of highly active antiretroviral therapy , a ganciclovir implant device is less effective than systemic therapy at improving survival and decreasing dissemination . postoperative complications directly associated with vitrasert implantation include cataract , vitreous hemorrhage , retinal detachment , endophthalmitis , and epiretinal membrane formation [ 9 , 10 ] . retisert is a sustained - release intravitreal implant containing 0.59  mg of fluocinolone acetonide coated with pva and silicon laminate . receiving fda approval in 2005 , it became the first intravitreal device for the treatment of chronic noninfectious uveitis . it is 5  mm long , 2  mm wide , and 1.5  mm thick with a release rate of 0.3 - 0.4  mcg / day for approximately 3 years . the device is inserted into the vitreous cavity and sutured to the sclera through a pars plana incision , a technique similar to the implantation of vitrasert . besides chronic noninfectious uveitis , studies have also shown the implant to be effective in edema from diabetes and central retinal vein occlusion ( crvo ) [ 11 , 12 ] . the clinical studies that resulted in the approval of retisert found significant reduction of recurrence of uveitis , determined by anterior chamber cell number and vitreous haze , in patients treated for noninfectious posterior uveitis . in this three - year study , recurrence rate was significantly decreased from 62% in the year prior to implantation to 4% , 10% , and 20% in the 1st , 2nd , and 3rd year after implantation , respectively . ocular complications encountered in implanted eyes , namely , lens opacification and increased intraocular pressure ( iop ) , were significant . in the same trial , 2-year safety data indicated that almost 100% of phakic patients would require cataract removal . this is a percentage much greater than that in patients with uveitis treated by steroids alone and indicates that the implant itself is contributing to increased lens opacity . by the end of the 3-year trial , 67% of implanted eyes had iop elevated by 10  mmhg or more from baseline . other postoperative adverse events encountered included eye pain ( 52% ) , conjunctival hyperemia ( 31% ) , conjunctival hemorrhage ( 29% ) , hypotony ( 11% ) , retinal detachment ( 4% ) , and endophthalmitis ( 1% ) [ 13 , 14 ] . a recent randomized , controlled , phase 2b/3 trial demonstrated a lower rate of recurrence of uveitis in fluocinolone acetonide implanted eyes ( 18.2% ) compared with those receiving standard of care , or systemic prednisolone or corticosteroid , treatment ( 63.5% ) . observed adverse effects were similar to those in prior clinical trials . the systemically treated group , however , encountered nonocular adverse events ( most commonly arthralgia and hypertension ) of 25.7% compared to 0% in the implant group . a large study enrolling 255 patients ( 479 eyes with uveitis ) , the multicenter uveitis steroid treatment ( must ) trial , also compared relative effectiveness of systemic therapy and fluocinolone acetonide implant in uveitis . it was shown that both approaches adequately controlled inflammation , but the implant group did so more often and earlier . visual acuity was equally improved in both groups at the conclusion of the two - year study . as demonstrated in previous studies , eyes in the implant group had high complication rates with 80% requiring cataract surgery , 61% requiring treatment for iop , and 16% with transient vitreous hemorrhage . another potential problem with the retisert implant is the dissociation of the 2 main components ( the suture strut and drug reservoir ) , which complicates removal and is potentially vision threatening . a retrospective study including 27 eyes found that 40.7% of the implants were dissociated at the time of removal or exchange . iluvien is an intravitreal implant for the treatment of chronic diabetic macular edema ( dme ) , defined as equal to or greater than 3 years of disease . it is 3.5  mm long by 0.37  mm wide and contains 190  mcg of fluocinolone acetonide . due to its small size , it can be injected through a 25-gauge needle , creating a self - closing hole . the material is nonerodible and does not require removal , potentially resulting in multiple devices in the eye if subsequent implants are required . besides use in dme , phase 2 studies in wet age - related macular degeneration ( amd ) , dry amd , and retinal vein occlusion ( rvo ) are also in process . iluvien is currently awaiting fda approval following the recent completion of phase 3 clinical trials , also known as the fluocinolone acetonide for diabetic macular edema ( fame ) trials . the fame study evaluated fluocinolone acetonide implants with release rates of 0.5  mcg / day and 0.2  mcg / day for 2436 months . at 36 months , the percentage of patients who had gained at least 15 points in best - corrected visual acuity ( bcva ) score was 28.7% in the low dose and 27.8% in the high dose implant groups compared to 16% in the sham group . improvement of at least 2 lines in the early treatment of diabetic retinopathy study ( etdrs ) acuity score was seen in a higher percentage of patients in the low dose group ( 13.7% ) than in the sham group ( 8.9% ) . as with the retisert implant , there was a high rate of increased iop and cataract formation . cataract surgery was performed in 80% , 87.2% , and 27.3% in the low dose , high dose , and sham groups , respectively . adverse events related to iop were more frequent in implant groups ( low dose , 37.1% ; high dose , 45.5% ) compared to the shame ( 11.9% ) . these results indicate that the iluvien implant , although with associated complications , is effective in dme , a disease that currently only has one fda approved treatment . i - vation is a helical sustained - release implant containing 0.925  mcg triamcinolone acetonide coated in titanium , pva , and eva . the implant elutes drug for up to 2 years . it measures 0.4  mm long by 0.21  mm wide and is implanted through a pars plana sclerotomy less than 0.5  mm in diameter . the helical shape is designed to increase surface area available for drug diffusion and anchor the device to the sclera , while the flat cap is meant to sit just beneath the conjunctiva . twenty - four - month interim results for phase 1 clinical trials of i - vation showed its effectiveness in treating dme . macular thickness , measured by optical coherence tomography , was decreased and visual acuity improved . phase 2b trials were terminated , and no further clinical trials have been completed . a novel port delivery system ( pds ) with ranibizumab designed to release 10  mg / ml over an extended period of time a phase 1 uncontrolled clinical trial on neovascular age - related macular degeneration was recently completed in latvia . the pds , initially filled with 150  mcg of ranibizumab , resulted in improved visual acuity , sustained decrease in macular thickness , and evidence of decreased choroidal neovascular leakage comparable to monthly injections . although final study data is pending , this technology shows promise in providing a long - term alternative to monthly ranibizumab injections . implants undergoing clinical trials in the united states for use in ocular disease include surodex ( oculex pharmaceuticals , sunnyvale , ca ) and verisome ( icon biosciences inc . , sunnyvale , ca ) . a third , ozurdex ( allergan inc . , irvine , ca ) , is already approved for several indications . these devices are composed of biodegradable polymers that allow dissolution of the implant , eliminating the need for extraction and decreasing risks associated with surgery . there are currently two such devices on the market , both containing dexamethasone as the active ingredient . ozurdex is a dexamethasone - containing intravitreal implant coated in biodegradable poly(lactic - co - glycolic acid ) ( plga ) . the implant is a 6.5  mm by 0.45  mm rod placed in the vitreous through the pars plana with a 22-gauge needle device . it contains 0.7  mg of dexamethasone and releases peak doses for 2 months followed by a lower dose for up to 4 additional months . when compared to triamcinolone and fluocinolone , dexamethasone is 5 and 20 times more potent , respectively , but has a shorter half - life than either . ozurdex is approved for macular edema following brvo or crvo and noninfectious posterior uveitis . in the huron study , a 26-week multicenter , randomized clinical trial , 229 patients with noninfectious intermediate or posterior uveitis were randomized into groups receiving implants with 0.70  mg dexamethasone , 0.35  mg dexamethasone , or sham . fifteen - letter improvement in bcva was achieved in the dexamethasone groups at a rate 2- to 6-fold greater than that achieved in the sham . in addition to improvement in visual acuity , the mean decrease from baseline central macular thickness was also found to be greater in implant groups compared to sham at 8 weeks . they were not significantly different at 26 weeks . percent of subjects with vitreous haze score of 0 at 8 weeks was 47% , 36% , and 12% , for those receiving high dose , low dose , and sham , respectively . adverse events included increased iop with 23% of the 0.7  mg treatment group requiring medication to lower pressure and one patient requiring laser iridotomy . cataract development was greater in treatment groups compared to the sham , but differences were not significant [ 23 , 24 ] . when the device was implanted in patients with macular edema due to retinal vein occlusion in the geneva study , similar improvements in visual acuity was not found to be significantly different between implanted and sham eyes by day 180 [ 25 , 26 ] . the solo study , a retrospective chart study designed to compare results from the clinical setting to those of the geneva study , also showed improvement in visual acuity and reduction of macular edema . early retreatment , defined as reinjection within the labeled 6-month interval , was performed in 40.7% and 50% of crvo and brvo eyes , respectively . several studies comparing the ozurdex implant with intravitreal ranibizumab in retinal vein occlusion are ongoing [ 2830 ] . additionally , favorable outcomes have been demonstrated in small case series in patients with persistent uveitic cystoid macular edema with history of pars plana vitrectomy , radiation macular edema , and macular edema from retinitis pigmentosa [ 3133 ] . it measures 1.0  mm by 0.4  mm and provides sustained release for 710 days following insertion into the anterior chamber . surodex has completed phase 3 clinical trials in the united states and has been approved in china , singapore , and several other countries . one study showed that , over 7 days , the insert achieved higher concentration in the eye than the maximum peak concentrations reached with topical dexamethasone drops following cataract extraction . a randomized clinical trial of surodex as a steroid drug delivery system for cataract surgery showed the implant to be safe and effective in reducing postoperative inflammation . their study included a group of subjects receiving two pellets in the anterior chamber , two pellets in the ciliary sulcus , and a control group that only received conventional topical 0.1% dexamethasone . lower flare scores were experienced in both implant groups compared to the control without any difference between the two placements . surodex was shown to be just as effective as topical 0.1% dexamethasone postcataract surgery without any significant improvement in decreasing flare . once injected with a 30-gauge needle , the material coalesces to form a spherule that sits in the posterior chamber and slowly degrades as medication is released . according to the manufacturer , its versatility allows it to deliver small molecules , peptides , proteins , and monoclonal antibodies . it can , furthermore , be formulated as a gel , liquid , or solid . a phase 1 multicenter study showed triamcinolone acetonide formulated with verisome to be well tolerated and without injection - related complications such as endophthalmitis or uveitis . it was also demonstrated to be effective in improving chronic cystoid macular edema ( cme ) due to retinal vein occlusion . a phase 2 clinical study for neovascular amd with ranibizumab formulated with verisome has also demonstrated its efficacy . results of the study indicated that frequency of ranibizumab injections might be decreased with this drug delivery system . several animal studies have shown that intravitreal delivery of cyclosporine can help control inflammation of the posterior chamber . a plga cyclosporine microsphere delivery system significantly decreased severity of cellular infiltrate , leukocyte number , and protein levels in eyes of rabbits with uveitis without long - term toxicity . a separate rabbit study demonstrated that cyclosporine a conjugated to a polycaprolactone ( pcl)/plga copolymer was more effective in treating chronic uveitis when compared to oral cyclosporine . cyclosporine a contained in a 6  mm diameter suprachoroidal implant placed in the deep sclera has also been found to be effective in controlling inflammation and maintaining vision in an equine recurrent uveitis model . plga implants containing 7  mg of indomethacin released over 3 weeks were evaluated in a postoperative model in rabbits . inflammation following capsulorhexis , phacoemulsification , and intraocular lens placement was significantly decreased , although the rate of posterior capsule opacification was unchanged from the control . more recent studies focus on surface indomethacin implants in treating inflammation in the anterior chamber [ 44 , 45 ] . particulate drug delivery systems utilize small biodegradable colloidal particles for long - term delivery of medication . microparticles and nanoparticles can further be subdivided into micro- or nanospheres , in which the drug is homogenously dispersed within a polymeric matrix , and micro- or nanocapsules , in which the drug is encased in a polymeric membrane . distinction is based on particulate size with microparticles generally accepted as 1 to 1000 microns in diameter and nanoparticles between 10 and 1,000 nanometers . liposomes are colloidal spheres made up of phospholipids , such as lecithin and phosphatidylcholine , which encapsulate therapeutic agents . hydrophilic drugs are tucked away within the lipid core of the sphere , whereas hydrophobic drugs remain soluble between the bilayer . because the phospholipids that compose these bilayers are naturally occurring , they are biocompatible with little toxicity and are capable of crossing hydrophobic membranes . limitations of this delivery method include short half - life , instability , and minimal control of drug release over time . those injected intravitreally are typically 100  nm to 400  nm in diameter according to the literature . use of liposomes as ocular drug delivery systems was first evaluated in superficial disease through topical instillation . in more recent years , intravitreal administration has been under investigation . currently , verteporfin ( visudyne , qlt inc . , vancouver , bc , canada ) , a benzoporphyrin derivative , is the only ophthalmic liposomal therapeutic agent approved . it is indicated in the treatment of neovascularization due to amd , pathologic myopia , or presumed ocular histoplasmosis [ 50 , 51 ] . liposomal amphotericin or ambisome ( gilead sciences , foster city , ca ) is indicated for the treatment of leishmaniasis and various fungal infections in immunocompromised individuals and patients with renal impairment . the liposomal formulation has fewer toxic effects than the native form thus allowing delivery of higher dosages intravitreally . improvement of drug pharmacokinetic properties by intravitreal injection of liposomal therapeutics has also been observed in amikacin , amphotericin b , bevacizumab , cidofovir , ganciclovir , ciprofloxacin , clindamycin , gentamicin , and tobramycin . microparticles are similar to liposomes in shape and size but have greater stability and capacity for carrying the drug . they are often composed of biodegradable polymers such as plga and polylactic acid ( pla ) . surface polymer modification can also enhance specific cell targeting and decrease degradation by the mononuclear phagocytic system . the components of microparticles are not naturally found in the body and their exact interactions with living cells and tissue are not clearly understood . to date , there are no microparticle drug delivery systems on the market . there are , however , many microparticle and nanoparticle therapeutic agents under investigation for improvement in long - term drug delivery . microcapsules containing tg-0054 , a water soluble antiangiogenic drug in phase 2 clinical trials , were shown to sustain in vivo release for 36 months when injected in the vitreous . these pla microparticles are , thus , a potentially useful formulation for long - term treatment of neovascular disorders of the eye . microspheres composed of plga and triamcinolone acetonide have shown potential utility in the treatment of dme in a nine - patient preliminary study . one  mg triamcinolone acetonide in a controlled - release microsphere system ( called retaac in the study ) was well tolerated and demonstrated superior long - term pharmacological performance compared to a 4  mg injection of triamcinolone acetonide . other microspheres developed for sustained ocular delivery of agents include those containing adriamycin , pegaptanib , and cyclosporine [ 6567 ] . microspheres composed of chitosan , a natural biodegradable polymer , for transcorneal delivery of acyclovir have also demonstrated prolonged drug release . nanoparticles have been used , experimentally , with several therapeutic agents for intraocular drug delivery . injection of tamoxifen incorporated into polyethylene glycol- ( peg- ) coated nanoparticles was found to be effective in the treatment of autoimmune uveoretinitis induced experimentally in rats . triamcinolone acetonide formulated in plga nanoparticles was recently studied in a rabbit model of endotoxin - induced uveitis . sustained - release nanoparticles , however , could potentially require fewer administrations and better patient compliance . intravitreally injected polyethylcyanoacrylate nanoparticles containing acyclovir and ganciclovir together showed sustained levels in rabbits but were also associated with cataracts and flare . periocularly injected recombinant pigment epithelium - derived factor ( pedf ) particles significantly reduced choroidal neovascularization in mouse and pig models by increasing retinal pedf levels [ 72 , 73 ] . a similar technology was used in a phase 1 clinical trial of adenoviral vector - delivered pedf in neovascular amd with promising results . no serious adverse events were noted , but mild , transient intraocular inflammation did occur in 25% of patients and increased iop in 21% . bevacizumab nanospheres composed of plga also demonstrated long - term release ( over 90 days ) . topical cyclodextrin nanoparticles for the treatment of dme are currently being studied in a phase 2 clinical study in comparison to dexamethasone . the structure of the eye makes it an organ that is well suited for local delivery of therapeutic agents . several intravitreal devices are approved for inflammatory processes as well as other pathologic conditions of the eye . intraocular nanoparticles and microparticles are also being developed and show great promise in sustained and targeted delivery of therapeutics . a multidisciplinary approach involving biomedical engineering , pharmacology , and molecular biology will continue to be critical in the design of implants for the treatment of ocular inflammation . as knowledge of these delivery systems and implants broadens , a safe and efficacious device that does not necessitate removal or surgical implantation may , in the future , be available as standard treatment for many ocular diseases .
the eye is a model organ for the local delivery of therapeutics . 
 this proves beneficial when treating vitreous inflammation and other ophthalmic pathologies . 
 the chronicity of certain diseases , however , limits the effectiveness of locally administered drugs . to maintain such treatments 
 often requires frequent office visits and can result in increased risk of infection and toxicity to the patient . 
 this paper focuses on the implantable devices and particulate drug delivery systems that are currently being implemented and investigated to overcome these challenges . 
 implants currently on the market or undergoing clinical trials include those made of nonbiodegradable polymers , containing ganciclovir , fluocinolone acetonide , triamcinolone acetonide , and ranibizumab , and biodegradable polymers , containing dexamethasone , triamcinolone acetonide , and ranibizumab . 
 investigational intravitreal implants and particulate drug delivery systems , such as nanoparticles , microparticles , and liposomes , are also explored in this review article .