Visual Prostheses: The Enabling Technology to Give Sight to the ...

Journal of ophthalmic and Vision research 2014; Vol. 9, No. 4494

INTRODUCTION

Owingtotheincrediblerecenttechnologicalprogressinthedevelopmentoftoolsanddevicesaimingatinterfacingtothenervoussystem,muchresearchhasbeenconductedoverthepastfewdecadestoeitherdeepenourunderstandingofthehumanneuralsystem,ortointerfacewiththenervoussystemforprostheticpurposes.Implantablemicrosystemsdesignedanddevelopedtoeitherstimulatethenervoussystemordirectly recordneuronalactivitieswithhighspatial resolutionarereferredtoasneuralprostheses.[1] Amongthesuccessfullycommercializedexamplesofneuralprostheses, one can name cochlear implants,whichprovidedpartialhearing tomore than120,000personsworldwideattheendofyear2008.[2]

VisualProstheses:TheEnablingTechnologytoGiveSighttotheBlind

Mohammad Hossein Maghami1, MS; Amir Masoud Sodagar1,2, PhD; Alireza Lashay3, MD Hamid Riazi‑Esfahani3, MD; Mohammad Riazi‑Esfahani3, MD

1Research Laboratory for Integrated Circuits and Systems (ICAS), Electrical Engineering Department, K.N. Toosi University of Technology, Tehran, Iran

2Electrical Engineering Department, Polytechnique Montreal, Montreal, Quebec, Canada 3Eye Research Center, Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran

AbstractMillionsofpatientsareeitherslowlylosingtheirvisionorarealreadyblindduetoretinaldegenerativediseases suchas retinitispigmentosa (RP)andage‑relatedmaculardegeneration (AMD)orbecauseofaccidentsorinjuries.Employmentofartificialmeanstotreatextremevisionimpairmenthascomeclosertorealityduringthepastfewdecades.Currently,manyresearchgroupsworktowardseffectivesolutionstorestorearudimentarysenseofvisiontotheblind.Asidefromtheeffortsbeingputonreplacingdamagedparts of the retinaby engineered living tissuesormicrofabricatedphotoreceptor arrays, implantableelectronicmicrosystems,referredtoasvisualprostheses,arealsosoughtaspromisingsolutionstorestorevision.Fromafunctionalpointofview,visualprosthesesreceiveimageinformationfromtheoutsideworldanddeliverthemtothenaturalvisualsystem,enablingthesubjecttoreceiveameaningfulperceptionoftheimage.Thispaperprovidesanoverviewoftechnicaldesignaspectsandclinicaltestresultsofvisualprostheses,highlightspastandrecentprogressinrealizingchronichigh‑resolutionvisualimplantsaswellassometechnicalchallengesconfrontedwhentryingtoenhancethefunctionalqualityofsuchdevices.

Keywords:ElectricalStimulation;MedicalImplants;NeuralProstheses;VisualProstheses

Correspondence to: MohammadRiazi‑Esfahani,,MD.EyeResearchCenter,FarabiEyeHospital,QazvinSq.,Tehran,Iran.E‑mail:[email protected]

Received:21‑09‑2013 Accepted:02‑03‑2014

Theideaofelectricallystimulatingthehumanvisualsystemwasfirstdescribedinthe18thcenturybyFranklin,[3] Cavallo[4]andLeRoy.[5]In1755,LeRoy[5]producedvisualsensationsoflightbypassinganelectricalchargethroughthe eye of a blindman. In 1929, Foerster, aGermanneurosurgeon, observed a visual neural response toelectricalstimulation,whenhispatientsawaspotoflightduringelectricalstimulationofhisvisualcortex.[6]Sincethen,theideaofrestoringvisiontotheblindhasmovedfromadistantdreamtonear‑futurereality.[7]

Failure in the operationof anypart of the visualsystem,asillustratedinFigure1,canpotentiallycauseblindness.Asidefromapproachessuchascellregrowth

J Ophthalmic Vis Res2014;9(4):494‑505.

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Visual Prostheses; Maghami et al

Journal of ophthalmic and Vision research 2014; Vol. 9, No. 4 495

using stem cells and semiconductor photodetectorarrays, implantablevisualprostheseshave exhibitedsuccessfulperformancethroughelectricalstimulation.[8] Implantablevisualprosthesismicrosystems,ingeneral,aimat receiving image information from theoutsideworldandaccordinglystimulatingaproperpartofthevisualsystem.Infact,avisualprosthesisisdesignedtobypassfailingpartsofthevisualpathwayanddelivertheimageinformationtotherestofthenaturalvisualsystemthatworksperfectly.Thiswillartificiallyproducevisualperceptioninindividualswithprofoundlossofvision.Althoughitisunlikelytorecreateperfectvision,artificialvisionsystemsmayevokeenoughphosphene(acollectionofthespotsoflightwhichareseenduringelectrical stimulationof thevisual cortex)perceptiontoperform every‑day tasks such as navigation, facerecognition,andreadinglarge‑sizetexts.[9,10]

Itisworthmentioningthattodevelopafullyfunctionalvisualprosthesis, in addition to thedevelopment ofelectronics andhardware required for this purpose,engineersneedtocollaboratewithspecialistsinclinicaland surgicalfields to formamultidisciplinary team.In addition tomakingdecisionsonmain issues suchas surgical and implantationprocedures, themedicalresearchteamalsoworksontheselectionofappropriatetypesoflabanimals,assessesandmonitorsissuesrelatedtothehealthandnormalbehaviorofthesubjectspre‑andpost‑implantation,andonthedesignanddevelopmentofclinicalteststoassesstheefficacyoftheimplant.Insummary, todevelop a visualprosthesis system forchronicoperation,closecollaborationbetweenspecialistsin both engineering (designing circuits and systems,fabricatingmicrostructuresandsignalprocessing)andmedical disciplines is inevitable. Figure 2 illustratesthe different design thrusts of a visual prosthesismicrosystem.Inthisreviewarticle,thegeneralstructureofavisual

prosthesisisstudied.Mainbuildingblocksofatypicalvisualprosthesis systemare thenbriefly introduced.Someof thekeydesignaspectsat thesystemlevelaswell as challenges faced in thedevelopment of such

Figure 1.Humanvisualpathway. Figure 2.Visualprosthesisdesignthrusts.

systemsaresubsequentlyaddressed.Finally,thelatestachievements in the design of visual prostheses byvariousresearchgroupsaroundtheglobeandsomeoftheirclinicaltestresultswillbereviewed.

VISUAL PROSTHESES, GENERAL DESIGN

Figure 3 shows the general architecture for visualprostheses of different kinds developed by severalgroupsworldwide.[11‑16] In avisualprosthesis system,anexternalvideocamera,usuallywornoneyeglasses,captures images from the visionfield of thepatientin theoutsideworld.Someexternalpre‑processing isperformedonrecordedimagesinordertoextractkeyimageinformationandhencereducetheamountofdatathatwillbetransmittedtotheimplant.Afterretrievalofdata on the implant side, an embeddedprocessorsendstheimageinformationtoastimulationback‑end,whichisinchargeofgeneratinganalogelectricalpulses.Usually,aflexiblecableconveystheseelectricaloutputstoanelectrodearraythatinterfacestothetargettissue.Inthefollowingsubsections,abriefdescriptionofthe

aforementionedvisualprosthesis electronichardwareunits aswell as some theassociateddesign concernsarepresented.

External Video Capture and ProcessingTheexternalmoduleofavisualprosthesisconsistsoftwoparts:Videocaptureunitandimageprocessingunit.Asaninseparablepartofanyvisualprosthesissystem,thevideocaptureunitcomprisesaminiaturizedcameramountedonthepatient’seyeglassesorhead.Differenttypesofcamerashavebeenusedforimageandvideocapture, e.g. photodiode arrays,[16] charge‑coupleddevices (CCDs),[17] and complementarymetal‑oxidesemiconductor(CMOS)cameras.[13,14]Duetothelimitednumberofelectrodesintheimplant,imageresolutionofthecameradoesnotimposeanyparticularconstraintsontheimageprocessingcapabilityoftheentiresystem.Temporal resolution isnot expected tobe aproblem





either,sincetheresponseoftypicalcamerasisusuallymuchfasterthanthatofthehumanvisualsystem.The externalunit of a visualprosthesis isusually

powered by batteries and the implanted electronicsreceivepowerthroughwirelessconnection.Consideringthe fact that the implantablemodule is preferred toberealizedwithsmallphysicalsizeandoperatewithlowpowerdissipation, anyattempt to reduce circuitcomplexityandalsopowerconsumptionoftheimplantiswelcomed.Forthisreason,compleximageprocessingtasksareusuallyperformedrightaftercapturingvideoinformationon thewearable externalmodulewherephysical size and supplying electric power are notmajor concerns. Edge detection and image qualityenhancement, zooming, contrast and brightnessadjustmentareamongtheimagepre‑processingtasksthatarerealizedontheexternalside.[18]Imageprocessingcomplexitydependsonthetypeoftechniquesemployedforenhancementofimagequalityandalsoonthepartofthevisualsystembeingstimulated(i.e.retina,opticnerve,orthevisualcortex).Theamountofdataconveying the imagecaptured

from theoutsideworldneeds tobe reduced inorderto complywith some system‑level restrictions andconstraints suchaswireless transmissionbandwidthandprocessing capabilitiesof the implantedmodule.Forthispurpose,bothresolutionandcolorinformationoftheimageislowered.Figure4showsasampleindoorpicture,withdifferentresolutionsandgraylevels.In imageprocessing, ingeneral,pixels areusually

intheshapeofsmallsquaressittingbyeachotherandforminga continuouspicture.This iswhile, invisualprostheses, eachpixel corresponds to a stimulatingelectrode. Patientsundergoing electrical stimulation

reportvisual sensations as amatrixof separate lightspots.Therefore,tovisualizewhatapatientcarryingavisualprosthesissees,itmightbemoremeaningfultopixelizepictureswithcircularshapesratherthanwithsquare‑shapepixels.Thequalityofvisionrestoredusingavisualprosthesisishighlydependentontheresolutionoftheimagedeliveredtothevisualsystemofthesubject.This resolution is indeeddefinedby the number ofstimulation sites on the target tissue. Simulations ofprostheticvisionsuggestthat600–1000electrodeswillberequiredtorestorevisualfunctiontoalevelthatwouldallow for reading, independentmobility, and facialrecognitioninretinalprostheses.[8]

Figure5showstwoCMOScameramodulesusedastheexternalvideocapturedevicebyoneoftheIranianresearchgroups (ResearchLaboratory for IntegratedCircuits andSystems [ICAS],K.N.ToosiUniversityof Technology, Tehran, Iran) in the field of visualprostheses.[19,20]Thesearebothwearablehardwarethatcan beused indynamic tests to evaluate the imageprocessingalgorithmsusedinresearchprototypesandalsoinrealvisualprostheses.

Wireless InterfaceDue to implant size limitations in visual prosthesesand because of the necessity to avoidingwires toreducetheriskofinfection,wirelessoperationofvisualprosthesesisinevitable.Aninductivelinkbetweentwoclosely‑coupledcoilsisthemostcommonapproachtowirelesslysendpoweranddatafromtheexternalworldtoimplantablebiomedicaldevices.[21‑23]Inthisapproach,asshowninFigure6a,aprimary(transmitting)coilisplacedontheoutsideandasecondary(receiving)coilisimplantedinsidethebodywiththethinlayersofliving

Figure 3.Generalarchitecturefordifferentkindsofvisualprosthesissystemsdevelopedbyseveralgroupsactivelyinvolvedinthisresearchdomain.





tissuesbetweenthem.Bothsidesofthelinkaretunedtothesameresonantfrequency,referredtoasthecarrierfrequency.Thewirelessinterfaceontheimplantcontainsapowerregulatorandadatademodulatorcircuitfortheretrievalofthereceivedpoweranddata,respectively.[24]

Recently, capacitive links have beenproposed asnovel alternativeswhich offer several advantagesover their traditional counterparts, i.e. the inductivelinks[Figure6b].Oneofthemostimportantadvantagesof the capacitive coupling approach is thehigh‑passnature of the link.[25,26] This is specificallywelcomedinvisualprostheses,where ratherhighdata ratesarerequiredtoenhancethequalityoftheimagestelemeteredtotheimplant.Besides size constrains, type of thewireless link

and the high data rate, one of themost importantissues inwireless telemetry is powerdissipation inthehumaneye.Thispowerdissipationmay result inexcessivetemperatureriseinbiologicaltissues,whichcanleadtotissuedamage.Therefore,whendesigningwireless interfaces, the amount of absorbed radiofrequency(RF)energyhastobeevaluatedandcomparedwith the human safety levels, usually expressed intermsof specific absorption rate (SAR) in associatedstandards.[27]Nowadays,SARcalculationsareperformedusinghigh‑resolution three‑dimensionalhumanbodymodelsbymostelectromagneticsimulators.[28,29]

Embedded Control UnitSimilartoalmostanyotherimplantablemicrostimulatingsystems, a visual prosthesis receives both setupand stimulationdata froman externalmodule. Theimplantablemicrosystem contains an embeddedcentralized controller,which is in charge of bothadministering the implant operation andgeneratingstimulation commands/data. Ingeneral, system levelspecifications of thedesigned embedded controllersto be used in any kind of visual prostheses are thesame.Thestimulationdataprovidedbytheembeddedcontrolleraresenttoastimulationback‑end,accordingtowhichappropriatestimulationpulsesaregeneratedanddeliveredtothetargettissue.Infact,theembeddedcontroller commands themicrostimulator togenerateelectrical pulseswith various amplitudes andpulsewidthsaccordingtothedatareceivedfromtheexternalmodule.Otherparameterssuchasinter‑phaseintervaland stimulation period are also controlled by thisblock.Moreover,theembeddedcontrollercontrolsthesequenceandorderofstimulationsforalltheelectrodes.As the embedded controller is designed to be

implantedinsidethebody,itneedstoberealizedwithsmall physical dimensions, consume small amountof power, andutilize a limited bandwidth for datatelemetryaccordingtofrequencyallocationregulations.Thereareotherconcernsinthedesignofanembedded

controller,whichincludeinterfacingwithothermodulesofthesystemthroughminimumpossibleinterconnects,andalsooperationwith sucha fastpace that allowsthe system to stimulate thenaturalvisual system forreal‑time,flicker‑freevideostreaming.Thisiswhytheresearchgroupsdevelopingvisualprosthesissystems

Figure 4. Various pixelized versions of different spatialresolutionswithdifferentgraylevels.[20]

Figure 5.CMOScamerahardwareusedbyICASvisualprosthesisteam(a)Firstgeneration,[19](b)Secondgeneration.[20]

ba

Figure 6. (a) Inductive coupling approach (b)Capacitivecouplingapproach.[25]

b

a





prefertodesigntheirownspecial‑purposecontroller[30,31] ratherthanusingoff‑the‑shelfcommerciallyavailable,generalpurposecontrollers.

Stimulation CircuitryIn amicrostimulation system, analog stimulationpulsesneed tobegenerated according to thedigitalcommandsanddataissuedbytheembeddedcontroller.Astimulationback‑endisinchargeofgeneratinganddelivering electrical stimulationpulses to the targettissue. In electrical stimulation, stimulations can, ingeneral, be in the formof current,voltage,or chargepulses.Fromthestandpointofthegeneralformofthestimuli,bothmonophasicandbiphasicpulsesareusedfor stimulation. Inmonophasic stimulation, for eachstimulation,asinglepulseisgeneratedtodeliveracertainamountofelectriccurrent,charge,orvoltagetothetargettissue. In this case, oneneeds to considerprovisionsfordischarging the stimulated area to avoiddamagetothetargettissuecausedbychargeaccumulation.Incharge‑balancedbiphasic stimulation [Figure7], eachstimulationpulse(anodicpulse)isfollowedbyapulseof reversepolarity (cathodicpulse) to collect chargesdelivered to the stimulatedareaby theanodicpulse.Amplitudeandtimingspecificationsofthestimulationpulsesneedtobetunedbasedonpatientfeedbackonvisualperception.Typicalpulseamplitudesarewithinthe10–600µArange,andthepulsewidthsrangefrom100 µs to around 2ms.A typicaldelayof 0–1ms isconsideredbetweentheanodicandcathodicpulses,andpulserepetitionrateforvisualprosthesesvaries from10Hzto125Hz.[32]

It should be noted that, even in charge balancedbiphasicstimulation,unavoidablesystematicmismatchesin thedesignandfabricationof thestimulationcausesmall residual charge at stimulation sites.Moreover,other issues such as charge leakage from adjacentstimulationsitesoveraperiodoftimemayresultinthebuildupofelectricchargeinthetissuebeingstimulated.Thus, charge cancellation circuitry is envisioned toperiodicallydischargestimulationsitesbyconnectingtheelectrodestothecommongroundpotential.

Microelectrode ArraysThe advent ofmicroelectrode arrays (MEAs)morethan 20 years ago led to steady advancement inthe development of neural interfaces aswell as ameaningful progress in neuroscience research. TheMEAsusedinadvancedneuralandvisualprosthesismicrosystems comprise multiple electrode sitesdevelopedforchronicimplantation.[33,34]Typically,anMEAisconnectedtotheelectronicsplatformusingaribboncablecontainingmultipleinterconnectscoatedbyorsandwiched inbetweenflexiblebiocompatiblepolymericprotectivelayers[Figure8].However,theprotective passivation layer,which is an insulatorfrom the standpoint of electrical conduction, isremoved from over the electrode sites in order toallow them to electrically interfacewith the targettissue.Silicon,[35]polyethyleneterephthalate(PET),[36] polyimide,[37,38]andliquidcrystalpolymer[39]areamongthematerialsusedastheelectrodesubstrate.Electrodesites are usuallymade of gold,[36] platinum,[40] and iridium‑oxide.[41]High‑temperature silicon oxide[42] and polymeric materials such as Parylene‑C, [41] epoxy‑based negative photoresist (SU‑8) [36] and polydimethylsiloxane (PDMS) [43] are used for passivation.Inprinciple, thehigher thenumberof stimulation

sitesare,thebettertheresolutionwillbe.Animmediateconsequenceoftheincreaseinthenumberofchannelsistheincreasedcomplexity,size,andpowerdissipationof the system,noneofwhich aredesirable invisualprostheses.

DIFFERENT APPROACHES TO THE DEVELOPMENT OF VISUAL PROSTHESES

Thevisualpathwayextendsfromphotoreceptorsintheretina to thevisual cortex in thebrain.Conceptually,to realize a visual prosthesis, the image informationrecorded from the externalworld can be deliveredto thenatural visual systemat anypoint along thispath(ofcourse,providedthatfromthereon,therestofthesystemishealthyandfunctioning).Hence,several

Figure 7.Diagramofbiphasiccurrentpulseinformofcurrent. Figure 8.Stimulationmicroelectrodearray.





approachesaretakentorestorevisiontotheblind,whichcanbecategorizedinto:Stimulationoftheretina,opticnervestimulation,andcorticalstimulation.Eachoneoftheseapproacheshasitsownattraction.Oneofthekeyreasons,ontheengineeringside,forthegreatinterestdirected towards retinal approaches is tomaximallybenefit from the imageprocessingperformed in thenaturalvisualsystem,hencereducingtheextentoftheimageprocessingexpectedfromthevisualprosthesis.Opticnervestimulationisanattempttodeliverimageinformationtothenaturalvisualsystemattheveryfirstplaceaftertheretina.Thisapproachcanbeapossibleoptionwhen the retina is atrophied. The corticalapproach is also considered as one of the possiblecandidates,tryingtobypassthevisualpathwayallthewaytothevisualcortex.

Retinal ProsthesisIthasbeenshownthatelectricalstimulationofretinalbipolar and ganglion cells yields visual sensation.Therefore,aretinalimplantforpatientssufferingfromRPandAMDseemstobefeasible.[8,11,12,16]Therearetwomain approaches to stimulate retinal ganglion cells:(I) Epi‑retinal stimulation, inwhich, the prostheticdeviceisattachedtotheinnerretinalsurface;and(II)the sub‑retinal approach,which involves implantinganelectrodearraybetweenbipolarcellsandtheretinalpigmentepithelium[11,12][Figure9].Inbothapproaches,generally,powerandinformationaredeliveredtotheelectrodearrayfromaseparatingprocessingunit.Whilethe electrode arrayneeds tobe attached to a certainareaintheretina,factorssuchassurgicaldetail,lengthof interconnections between the electrode array andthe implantedelectronicpackage, and thermal safetyconsiderationsdeterminewheretheelectronicsplatformwillbeplaced.[11,12]

Anumber of retinal prosthesis projects are beingpursued through both epi‑retinal and sub‑retinalapproaches.Theadvantagesoftheepi‑retinalapproachincludethefollowing:(1)Theprocedureforimplantationis relatively straightforward and placement on theepi‑retinal surfacewill not separate the retina fromretinalpigmentepitheliumandchoroid.(2)Epi‑retinalplacementallows for thevitreous toact as a sink for

heatdissipation from themicroelectronicdevice.[44,45] Disadvantagesofthisapproachinclude:(1)Requirementof techniques thatwillprovideprolongedattachmentofthedevicetotheinnerretinaonthemedicalside,[46,47] and(2)stimulationattheoutputoftheretina(ganglioncells)ontheengineeringside,whichwillrequiremoresophisticated imageprocessing to account for retinaalgorithms.[48]

Placementof theprosthesis in the sub‑retinal spacehas advantages such as closerproximity to thenextsurviving layers of neurons in the visual pathway(i.e.bipolarcells).[49,50]Stimulationatthebipolarcelllevelwillallowsignificantretinalprocessingtoshapetheneuralresponse.Placinganelectrodeinterfaceinthesub‑retinalspacewilluse the retina tohold theelectrode incloseproximitytotheelectrode.[49]Also,fixationofanimplantinthesub‑retinalspacemightbemorestablethantackingittotheepi‑retinalsurface.Disadvantagesofthisapproachincludethelimitedsub‑retinalspacetoplacetheelectronicsaswellasthecloseproximityoftheretinatotheelectronicswhichwouldincreasethelikelihoodofthermalinjurytoneuronsandconsequently limit the thermalbudgetoftheimplant.Ifthesub‑retinalimplantisonlyanelectrodearraywiththeelectronicsoutsidetheeye,thentheimplantwillhaveacableacrossthesclera,whichmayresultinatetheringeffecton thecable.[51]Furthermore, thiscable,overthelongterm,increasesthelikelihoodofsub‑retinalhemorrhageandtotalorlocalretinaldetachment.There is another sub‑retinal approach, inwhich a

microchip containingphotodiodearrays is implantedunderthetransparentretinatosubstitutethedegeneratedphotoreceptors. The implant is, indeed, a singlecomponent in charge of converting incident light toelectricalcurrentanddeliveringtheresultingelectricalstimulitotheretina.[16]Whilealloftheapproachesonthedevelopmentofvisualprosthesesrequireexternalimageanddataprocessingdue to bypassing retinal imageanalysis, implantablephotodiodearraysare intendedtoreplacethefunctionofdegeneratedphotoreceptorsbydirectly translating the image into small electricalstimulationswith no need for additional electroniccircuitry.Otheradvantagesofthisapproachincludeeasyplacement,fewercomponents,andsincenovideocamera

Figure 9.Retinalvisualprosthesis. Figure 10.Opticnervestimulation.





isused,thepossibilityofusingeyemovementtolocateobjects.Initsoriginalform,theprincipaldrawbackofthissystemistheinabilityofthephotodiodestogeneratestrongenoughcurrentstostimulatetheadjacentneuronsbyusingmerelytheincidentlight.Also,placementofthephotodiodearraycomponentcoulddamagetheretinathroughpigmentepitheliumseparationorobstructionofbloodflowfromtheretina.

Optic Nerve StimulationTheopticnerve,which is about1–2mm indiameter,servesasa compact conduit forall the information inthevisualscene.Thismeansthatelectricalstimulationofasmallareaoftheopticnervewouldbeexpectedtoactivatealargesegmentofthevisualfield.Stimulationoftheopticnerveisrealizedusingacuffelectrodeencirclingit,asillustratedinFigure10.Sincetheelectrodesareontheoutsideofaverydenselypackednerve(~1.2millionfiberswithinthenerve),focalstimulationanddetailedperceptionaredifficulttoachieve.[52]Thisapproachalsorequiresreal‑timeimagecaptureandprocessing,andalsoatelemetrylinkforthetransferofpoweranddatatotheelectronicimplant.Asaresultofcompletelybypassingtheretina,notonlythisapproachcanbeusedforpatientswithretinaldegeneration,italsooffersarelativelysaferandeasierimplantationprocedurecomparedtoretinalapproaches.Thisapproachis,however,ratherimmaturecomparedtoitscounterparts.Thepossibilityofgeneratingpatternvisionbyelicitingspatiallyadjacentphosphenesusingopticnervestimulationisstillunclear.[53]

The Cortical ApproachHistorically, there has been notable research in thedevelopmentofavisualprosthesisthatstimulatesthevisualcortex.Startinginthe1960’s,severalreportswerereleasedon the inductionofphosphenes inpatientswith profound blindness.[54,55] Patients reported theabilitytoreadBraillepatterns,realletters,driveacarinaparkinglot,andwalkaroundaroomusingthiskindofprostheses.[56‑58]

Figure 11.Corticalapproach.

Figure 12.Number of scientific and technical documentspublishedwiththekeywords‘visual’and“prosthesis”intheirtitlesorabstracts.

Withouttakingsomanytechnological,surgical,andcognitivechallengesintoconsideration,stimulationofthevisualcortex[Figure11]isbelievedtobesuccessfulin restorationofvision for theblinddue todifferentcauses,includingthosesufferingfromdamagetoboththe retina andoptic nerve.However, for thosewhoare eligible to use retinal prosthesis or optic nervestimulation,corticalvisualprosthesesmightnotbethefirstchoice.Theratherhighsurgicalriskthatapatientwithanotherwisehealthybrainneedstotake,andalsotheextracomplicatedimageprocessingthattheartificialsystemneedstohandleareamongthereasonswhythecorticalapproachhasnotbeenwelcomedascomparedwithother approaches.[7,10,59‑62]Among the significantadvantagesofthecorticalapproachoveritscounterparts,onecanpointtothereducedpowerrequirementsperstimulationsite,morepredictablephosphenegeneration,lessphospheneinteraction,absenceofflicker,andthepossibilityofpackingmorestimulationchannelstherebyincreasingresolution.[63]

VISUAL PROSTHESES PIONEERING RESEARCH GROUPS

Overthepastdecade,severalresearchteamshavebeeninvolved in the development of functioning visualprostheses.BasedonasearchwithinElsevier’sScopusdatabase,Figure12showstheexponential‑likegrowthofscientificandtechnicaldocumentspublishedon‘visual’and‘prosthesis’overthepastdecades.Contributionofpioneercountriesinthefieldofvisualprostheses,intermsofpaperspublishedduring2008–2013[64] is illustrated in Figure13.Morethan55%ofthesepublicationsareinthefieldofmedicine.[64]

TheArtificial Retina team is one of the pioneergroups in the development of implantable visualprostheses. ProfessorsM.Humayun andE.DeJuanof the Doheny Eye Institute at the University ofSouthern California (USC), Dr. R. Greenberg ofSecond Sight company, and ProfessorW. Liu oftheUniversity of California at SantaCruz (UCSC)are the original inventors of the active epi‑retinalprosthesis. They demonstrated proof of principle





in acute patient investigations at JohnsHopkinsUniversity in the early 1990s. In the late 1990s, thecompanySecondSightwasformedbyDr.Greenbergalongwithmedicaldeviceentrepreneur,A.Mann,todevelopachronicallyimplantableretinalprosthesis.Theirfirstgenerationimplanthad16electrodesandwasimplantedin6subjectsbetween2002and2004.Thesesubjects,whowereallcompletelyblindpriortoimplantation,couldperformasurprisingarrayoftasksusingthedevice.[7]In2007,SecondSightbeganatrialofitssecondgeneration60‑electrodeimplant,namedArgusII, intheU.S.andEurope.Intotal,30subjectsparticipatedinthestudiesspanning10sitesin4countries.ThepreliminaryresultsshowthattheArgus II systemprovides some functionalvision toblindsubjects.[59]Inthespringof2011,aftermorethantwodecadesofresearchanddevelopmentinthefieldofvisualprosthesis,ArgusIIwasapprovedforclinicalandcommercialuseinSwitzerland,France,andtheUK.[65]SecondSightCompanylaunchedtheproductlater the same year. ThreemajorU.S. governmentfundingagencies(NationalEyeInstitute,Departmentof Energy, andNational Science Foundation) havesupportedtheworkatSecondSightCompany,USC,UCSC,CalTech,andotherresearchlaboratories.[7]

To date, Second Sight has sponsored clinicalt e s t s approved by the US Food and DrugAdministration (FDA) for theArgus I and IImodelsystems.TheArgusIIretinalimplantwassuccessfullyimplantedin2013intwopatientssufferingfromRPinSaudiArabia.ThepatientswereonemanandonewomanandhadtheArgusIIretinalprosthesissystemimplantedinoneeye.Averagelengthofsurgerywas3h.Now,thepatientscanrecognizethepresenceofpeopleinfrontofthemandareabletodetectbuildingsoutside,aswellasflowersingrassareas.[7] As research

ontheimplantprogresses,upgradedperformancefortheprocessingofvisual informationareexpected inthefuture.TheSecondSightCompanyexpectsfutureupgradedmodels to givepatients the ability to seefaces, colorandalsonightvision.[7]Thenext stepoftheArgusprojectistoproducea256‑electrodedeviceready for extensive preclinical testing.[11] Their newdesignhas ahighly compact arrayand this array isfour timesmoredenselypackedwithmetal contactelectrodes than that of theArgus II.[11] Simulationsand calculations indicate that the 256 electrode device shouldprovideimprovedvisionforpatients.InterestedreadersarereferredtothelatestnewspublishedbytheSecondSightCompany’swebsiteformoreinformationandalsoclinicalstudies.[7]

TheBostonRetinal Implant (USA) is involved inthe development of a sub‑retinal visual prosthesis.The i r min ia tu r i zed , he rmet i ca l l y ‑ encased ,wirelessly‑operated retinal prosthesis has beendeveloped for preclinical studies in a Yucatanminipig.The implantpartof this systemattaches tothe outer surface of the eye and electrically drives a microfabricatedthinfilmpolyimidearrayofsputterediridiumoxidefilmelectrodes.Thisarrayisimplantedinto the sub‑retinal space using a customized abexterno surgical technique. The implanted deviceincludes a hermetic titanium case containing a15‑channel stimulator chip aswell as somediscretecircuit components. The operation of this implanthasbeenverifiedintwopigsforupto5½monthsbydetectingstimulusartifactsgeneratedbytheimplanteddevice.[12,60]

C‑Sight(ChineseProjectforSight)isamultidisciplinaryresearch project on visual prosthesis founded inChina.ThegoaloftheC‑Sightprojectistodevelopanimplantable optic nerve stimulationmicroelectronic

Figure 13.Contributionofthecountriesactivelyinvolvedinresearchonvisualprosthesesintermsofthenumberofpaperstheypublishedduring2008–2013.





medical device thatwill restore vision to a limitedextenttotheblind.Intheirapproach,theycoupletheencodedelectricalstimuliintoaxonsofganglioncellsbypenetratingmulti‑electrodearraysintotheopticnerve.Feasibility of this approach has been studiedusinganimalexperiments.[13,66]

Asanexampleofcorticalvisualprosthesis,onecanname the systemdevelopedby theDobelle Instituteunder direction ofWilliamDobelle (1941–2004). Inthiswork, visual information are transcutaneouslytransferred from an external image capture andpreprocessingunittoanimplanted64‑electrodearray.Thepatientcarryingthisprosthesiswasabletoreadtwoinchtalllettersatadistanceoffivefeet,representingavisualacuityofabout20/400.Althoughtheelectrodearrayproduces tunnelvision, the subjectwasable tonavigateinunfamiliarenvironments.[54]

Whilealloftheabovementionedapproachesworkon thesamebasicconcept illustrated inFigure3, the

Retina Implant group inGermany tries to restorevisionusing a subretinalmicrophotodiode array. Inthefirstclinicalpilotstudy,thearraywasimplantedin11patientssufferingfromphotoreceptordegeneration.Inone subject,whose implantwasplacedunder themacula, visual acuity of 20/1000was reported. Theresults of this studydemonstrated, for thefirst time,that sub‑retinalmicroelectrode arrayswith 1,500photodiodes can create detailedmeaningful visualperception.[10,16] In another study, the photodiodeswere implanted in 9 blind patients. The patientsreceivedthesubretinalvisualimplantinoneeyeandtheother eyewas alwaysoccludedduring the tests.Noneofthesubjectshadothereyediseasesthatmightaffectthevisualpathway.Inthisstudy,visualacuitymeasurementwithLandoltC‑ringsuptoSnellenvisualacuity of 20/546 (corresponding todecimal 0.037orcorresponding to 1.43 logMAR [minimumangle ofresolution])wererestoredviathesubretinalimplant.[67]

Table 1. Brief overview of current artificial vision projects around the world

Country University Researchers Group name Approach Latest Pubs.

USA UniversityofS.California(DohenyRetinaInstitute)andUniversityofCalifornia

M.S.Humayun,W.Liu,andJ.D.Weiland

ArtificialRetina Epi‑retinal [11,59,68,69]

Germany RWTHAachenUniversityandFraunhoferInstituteofMicroelectronic

W.Mokwa N/A Epi‑retinal [41,70,71]

Germany IMIIntelligentMedicalImplantsandInst.ofMicroelectronics,UniversityofUlm

R.HornigandM.Ortmanns

IntelligentMedicalImplants

Epi‑retinal [72,73]

Iran K.N.ToosiUniversityofTechnology A.M.Sodagar,A.LashayandM.Riazi

ICAS Epi‑retinal [31,36,74‑77]

USA MassachusettsInstituteofTechnologyandMassachusettsEyeandEarInfirmary

J.Rizzo,J.WyattandW.A.Drohan

BostonRetinalImplant

Sub‑retinal [12,60,61]

Germany TübingenUniversity,EyeHospital E.Zrenner RetinaImplant Sub‑retinal [10,16,62]USA LoyolaUniversityofChicago,Schoolof

MedicineAlan and Vincent Chow

ArtificialSiliconRetina

Sub‑retinal [50,78]

Japan OsakaUniversity,MedicalSchool Y.Tano,T.FujikadoandH.Sawai

JapaneseConsortiumforanArtificialRetina

Suprachoroidal‑ transretinal stimulation

[79,80]

USA StanfordUniversity D.Palanker OptoelectronicRetinalProsthesis

Photovoltaicretinalprosthesis

[81,82]

Australia Centre for Eye Research Australia at the UniversityofMelbourne,theBionicEarInstituteandtheVisionSciencesGroupattheAustralianNationalUniversity

N.LovellandG.Suaning

Australian Vision Project

Opticnervestimulation/retinal

[83,84]

Belgium CatholiqueUniversitédeLouvain C.Veraart VisionProject Opticnervestimulation

[85]

China ShanghaiJiao‑TongUniversity X.ChaiandQ.Ren C‑Sight Opticnervestimulation

[13,66]

Portugal DobelleInstitute W.Dobelle N/A Cortical [3,54]Canada PolytechniqueMontrealUniversity M.Sawan Polystim Cortical [14,86]USA UniversityofUtah R.Normann UtahArtificial

VisionCortical [63,87]

USA IllinoisInstituteofTechnology P.R.Troyk N/A Cortical [88,89]





Lightperception,lightlocalizationandmotiondetectiontestswerealsoperformedonthesubjects.Thisstudyhasshownthatthedesignedsystemcanrestoreusefulvisionindaily lifeforat least two‑thirdsof theblindpatientsinvestigated.Abriefoverviewofcurrentartificialvisionprojectsis

presentedinTable1.Interestedreadersarereferredtothelatestpaperspublishedbyeachresearchgroupformoreinformation.

SUMMARY

Areviewofthevisualprosthesesintendedtorestorefunctional vision is providedherein. Basic conceptsin research on these implantable microsystemsare studied, and general issues in their design anddevelopmentarediscussed.Differenttypesofvisualprostheses, from the standpoint of how theyworkandhowtheyareused,areintroduced.Subsequently,latestachievementsinthedesignofvisualprosthesesbypioneerresearchgroupsandcompaniesaroundtheglobeandsomeoftheirclinicaltestresultsarebrieflyreviewed.

ACKNOWLEDGMENTS

TheauthorswouldliketothanktheICASvisualprosthesisteammembers:M. A. Shahzeidi, A. Shaker,H. Salehi,L. Saadati‑fard, S. Novin,M. Takhti, E. Ashoori, andF.Asgarian for their technical contribution; S. SharafzadehandZ.Erfani‑Gholampourfortheirassistanceinartworkandcomputergraphics;andalsoA.Sheikholeslami,J.Maghami,andF.Khosravifortheirhelpandsupport.

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How to cite this article: Maghami MH, Sodagar AM, Lashay A, Riazi-Esfahani H, Riazi-Esfahani M. Visual prostheses: The enabling technology to give sight to the blind. J Ophthalmic Vis Res 2014;9:494-505.

Source of Support: Nil. Conflict of Interest: None declared.

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