REVIEW

A Review of Robotic and OCT-Aided Systemsfor Vitreoretinal Surgery

Elan Z. Ahronovich . Nabil Simaan . Karen M. Joos

Received: January 18, 2021 /Accepted: February 27, 2021 / Published online: April 3, 2021� The Author(s) 2021

ABSTRACT

The introduction of the intraocular vitrectomyinstrument by Machemer et al. has led toremarkable advancements in vitreoretinal sur-gery enabling the limitations of human physi-ologic capabilities to be reached. To overcomethe barriers of perception, tremor, and dexter-ity, robotic technologies have been investigatedwith current advancements nearing the feasi-bility for clinical use. There are four categoriesof robotic systems that have emerged throughthe research: (1) handheld instruments withintrinsic robotic assistance, (2) hand-on-handrobotic systems, (3) teleoperated robotic

systems, and (4) magnetic guidance robots. Thisreview covers the improvements and theremaining needs for safe, cost-effective clinicaldeployment of robotic systems in vitreoretinalsurgery.

Keywords: Image-guided surgery; Medicalrobotics; Micromanipulator; Ophthalmicsurgery; Ophthalmology; Optical coherencetomography; Telemanipulation; Vitreoretinalsurgery

E. Z. AhronovichAdvanced Robotics and Mechanism Applications(ARMA) Laboratory, Department of MechanicalEngineering, Vanderbilt University, Nashville, TN37235, USA

N. SimaanAdvanced Robotics and Mechanism Applications(ARMA) Laboratory, Department of MechanicalEngineering, Department of Computer Science,Vanderbilt University, Nashville, TN 37235, USAe-mail: nabil.simaan@vanderbilt.edu

K. M. Joos (&)Vanderbilt Eye Institute, Vanderbilt UniversityMedical Center, Nashville, TN 37232, USAe-mail: karen.joos@vumc.org

K. M. JoosDepartment of Biomedical Engineering, VanderbiltUniversity, Nashville, TN 37235, USA

Adv Ther (2021) 38:2114–2129

https://doi.org/10.1007/s12325-021-01692-z

Key Summary Points

To overcome the barriers of perception,tremor, and dexterity in vitreoretinalsurgery, robotic technologies have beeninvestigated with current advancementsnearing the feasibility for clinical use.

There are four categories of roboticsystems that have emerged through theresearch: (1) handheld instruments withintrinsic robotic assistance, (2) hand-on-hand robotic systems, (3) teleoperatedrobotic systems, and (4) magneticguidance robots.

The future of vitreoretinal surgery mayinclude some of the robotic systems orimplementations of technologyintroduced in the development of therobots.

Limitations of surgical robots includebarriers presented by sensor-actuation lagthat can be limited by using highsampling frequencies. Also, heavycomputational demands from visualfeedback technologies currently makereal-time integration challenging.

Clinical surgical robotics will likely usetechnologies such as optical coherencetomography and tool tip forcemeasurements to add accuracy.

DIGITAL FEATURES

This article is published with digital features,including a summary slide, to facilitate under-standing of the article. To view digital featuresfor this article go to https://doi.org/10.6084/m9.figshare.14125301.

INTRODUCTION

Needs and Challenges in OphthalmicSurgery

Despite vast advances in vitreoretinal surgerysince Machemer et al. [1], it presents challengesto surgeons in terms of precision, perception,and manipulation dexterity. A typical setupduring these procedures involves multiportaccess into the vitreous cavity with thin tools(e.g., picks, graspers, light source). Visualizationof the retina through a surgical microscope isachieved through the pupil with adding afocusing lens on or above the cornea. Surgeonshave to stabilize the eye while operating one totwo instruments within the vitreoretinal space.Surgical tools generally lack distal dexterityowing to their small size (generally less than900 lm in diameter) and they have to bemaneuvered under deficient perception condi-tions. For example, the visualization of theanatomy is limited through a dilated iris, espe-cially if dilation is poor. Tool shadows are hardto perceive because of complex lighting condi-tions with chandelier illumination or a smallmoving endoilluminator light held in the sur-geon’s second hand and the retinal anatomypresents semitransparent features (e.g., retinalmembrane) that can be difficult to see. Added tothese challenges is the difficulty of measuringtool tip interaction forces because of the inter-ference from tool–trocar friction forces as con-cluded by Jagtap et al. [2]. Further, Jensen et al.[3] showed that the delicate anatomy of theretina can apply reaction forces less than7.5 mN for 77% of the duration of a vitreoreti-nal procedure which was perceived by the sur-geon only 20% of the time. This reviewdescribes current retinal surgical limitations,the parallel developments of optical coherencetomography (OCT) and surgical robotics, andthe intersection of the two technologies whichhave the potential to revolutionize patient care.

Success of many vitreoretinal proceduresdepends on safe manipulation of the delicateanatomy of the retina. For example, epiretinalmembrane peeling requires careful peeling of alayer that can be on average 61 ± 28 lm thick

Adv Ther (2021) 38:2114–2129 2115

[4] while avoiding trauma to the underlyingretinal anatomy. Treatment of retinal detach-ments requires maneuvers using picks andminiature graspers/cutters while avoiding exac-erbating the retinal detachment and avoidinginadvertent touching of the lens or causingretinal hemorrhage. Previous experimentalcharacterizations of physiologic tremors illus-trate the challenge of accomplishing such pre-cise tasks. For example, the average root meansquare (rms) amplitude of tremor with a four-subject user study ranged between 14 and142 lm [5] when holding a tool still andbetween 59 and 341 lm when actuating amicrosurgical grasper. In another exampleSingh and Riviere [6] tracked the tool motionduring epiretinal membrane peeling and repor-ted the rms amplitude of tremor at 38 lm for asingle-subject study. These reported magnitudesof tool tremor are large enough to makemicroretinal procedures exceedingly challeng-ing. To overcome tremor, four approaches usingrobotics were considered in the literature. In thefirst method, a handheld miniature roboticplatform was used for tremor cancellation oftracked instruments. Examples of this approachinclude Riviere et al.’s Micron [7], Song et al.’sSMART OCT-based device [8], and Cheon et al.’sOCT-guided depth-locking handheld microin-jector [9]. In the second method, a hand-on-hand approach is used where the surgicalinstrument is held by a robot and the surgeon’shand. Forces by the surgeon’s hand are used tocommand the robot (tool) motion while alsoproviding tremor filtration, Taylor et al.’sSteady-Hand eye robot [10] for example. A thirdapproach using telemanipulation with a sur-geon controlling a robotically guided surgicaltool via a control station detached from therobot was initially explored by Charles [11], Weiet al. [12], Yu et al. [13], and Meenink et al. [14].Finally, the fourth approach using extraocularmagnetic fields achieves manipulation of twotypes of intraocular robots. Kummer et al. [15]demonstrated intraocular microcapsule robotsand Charreyron et al. [16, 17] demonstratedsteerable magnetic-tipped catheters for druginjection delivery and retinal vein cannulation.

Vitreoretinal surgery is also complicated byperception barriers owing to operating through

a microscope and due to limited tactile feed-back. Typically, humans rely on a tactileresponse as a form of confirmation of contact-ing an intended target when performing a tasksuch as surgery. However, the delicate intraoc-ular anatomy does not produce reaction forcesgreat enough to overcome the friction betweena surgical tool and trocar to reach a level per-ceptible to humans. With this lack of tactilefeedback, surgeons are forced to rely heavily onvisual cues to discern tool proximity and con-tact of the surgical tools with the anatomy [3].However, intraocular visualization via a surgicalmicroscope has limits of useful depth percep-tion and the visible field of view is restricted bythe dilated iris. In addition to manipulatinginstruments inside the eye, surgeons may alsotilt the eye under the microscope. In some cases,the target anatomy is difficult to visualize usingwhite-light imaging. For example, epiretinalmembranes are mostly transparent which stan-dard light microscopes are incapable of visual-izing without the addition of a steroidsuspension or indocyanine green (ICG) to stainthe membranes. Surgeons may also use endo-scopes for auxiliary peripheral visualization;however, these scopes have limited resolutionscompared to current microscopes. To addressthe challenge of depth perception, previousinvestigations have augmented instrumentswith OCT probes. For example, Balicki et al. [18]used an A-scan OCT probe to maintain thedistance of a robotic-controlled tool tip fromretinal anatomy. Yu et al. [19, 20] used forcepsintegrated with a B-mode OCT probe for depthperception feedback. In Yu et al. [19] it wasshown that OCT feedback improved depthperception and success of approaching a surfaceand peeling a surface membrane.

In addition to precision and perceptionchallenges, there are challenges due to rigidinstrumentation offering limited maneuver-ability. Vitreoretinal surgical tools are generallyslender instruments with rigid shafts. Theseinstruments are constrained to the traditionalfour-DOF (degrees of freedom) motions avail-able to minimally invasive instruments (tilt intwo directions and rotation about and transla-tion along the longitudinal axis of the tool). Asa result, the tool tip dexterity of these

2116 Adv Ther (2021) 38:2114–2129

instruments is quite limited. One can reach aparticular site, but with limited control of tooltip orientation. Surgeons have to carry out sur-gical maneuvers of lifting membranes withpicks and graspers despite their limited distal tipdexterity and contend with the need forbimanual manipulation in order to stabilize theeye while operating tools inside it. Ikuta et al.[21] proposed the use of manual active bendingforceps, but the current clinical repertoire ofsurgical forceps still remains predominantlywithout active distal bending. The four scenar-ios of ocular and intraocular manipulation havebeen considered [22] with an emphasis onquantifying the possible benefits of instrumen-tation with intraocular dexterity. It was shownthat adding a single DOF of bending sidewayscan increase orientational dexterity, comparedto rigid instruments, by 31.6% and 57.7% fortranslational and rotational manipulation,respectively. Several tools and robotic instru-ments have been considered to overcome theproblem of intraocular dexterity. In Simaanet al. [23] the concept of intraocular dexteritytools using continuum bending cannulas wasintroduced and later implemented by Wei et al.[12, 24] and Yu et al. [13]. He et al. [25] intro-duced a prototype of a 0.9 mm handheld con-tinuum robot offering intraocular dexterity thatwas later integrated with a robotic platform bySong et al. [26].

The aforementioned challenges of tremor,limited visual and tactile perception, and tooltip dexterity can be alleviated in several ways.For example, active tools can limit the effects ofhuman tremor to increase surgical precision byfiltering sensor input to produce tremorlessactuator control. Visual perception can be aug-mented using OCT to obtain cross-sectionalimaging of tissue yielding a richer set of infor-mation of target anatomy. Using sensors thatcan detect forces imperceptible to humansenhances a surgeon’s effective tactile percep-tion. For higher dexterity, continuum segmenttools offer higher ranges of motion withmanipulation directly by a surgeon or attachedto robotic systems for greater levels of manipu-lability and accuracy. In the following we dis-cuss some of the tools that have been developedto address the three main areas outlined above

limiting vitreoretinal surgery and discussprospective areas of development to furtherlessen these constraints.

METHODS TO IMPROVEVISUALIZATION: OPTICALCOHERENCE TOMOGRAPHY (OCT)

OCT is a standard diagnostic and surgicalplanning ophthalmic tool that can developcross-sectional images of tissue using lightreflectance. Dayani et al. used a handhelddevice during planned surgical procedureinterruptions [27]. Binder et al. first used amicroscope-mounted unit following surgicalmanipulations [28]. The Duke [29–38], Cleve-land Clinic/Case Western Reserve [36, 39–47],Vanderbilt [48], and international groups[28, 49–52] developed improvements for themicroscope-mounted intraoperative OCT sys-tems with commercial US Food and DrugAdministration (FDA)-approved systems avail-able for the operating room [53].

Non-OCT surgical intraocular endoscopesare FDA-approved [54–60], but there is not yetan approved facile ophthalmic OCT probe toenable peripheral retina visualization as well asbypass corneal and lenticular opacities that mayhinder direct central visualization [61]. Iftimiaet al. [62] developed an A-scan 250 lm OCTprobe for one-dimensional measurement oftissue.

Balicki et al. [18] reported an intraocularcommon path A-scan OCT probe. A 20-gaugecoplanar probe was developed which success-fully guided the depth of mid-infrared laserincisions of the retina [63]. The OCT-imagingcomponent alone was housed within a 25-gaugetube which was readily amenable to imagingthrough the more recent 23-gauge and 25-gaugetrocars preferred for contemporary retinal surg-eries [64]. Addition of a needle [65] or forceps[19] increased the size only to 23 gauge. ThisOCT probe has been added to robotic platformsdescribed in the following section.

Ray et al. presented a custom mount thatattached the Bioptigen handheld probe to anophthalmic surgical microscope [66]. OCTimages from 24 patients undergoing macular

Adv Ther (2021) 38:2114–2129 2117

hole or epiretinal membrane surgery were ana-lyzed with subsequent quantitative measure-ment of geometry and retinal thicknessproviding insight into the anatomical changesin the retina resulting from macular surgery andverifying surgery completion. The feasibilityand safety of microscope-mounted OCT inprospectively and retrospectively enrolled eyesduring several ophthalmic surgeries was repor-ted, and it enhanced surgeons’ understandingof the underlying anatomy in more than 40% ofthe cases during lamellar keratoplasty and reti-nal membrane peeling [67–69].

Microscope-integrated systems have beendeveloped which combine the OCT and surgicalmicroscope optical paths to enable imagingsimultaneously with surgical maneuvers[30, 31, 41, 42, 70, 71]. The Duke research pro-totype [30] was clinically evaluated in a studyinvolving eight patients undergoing surgery formacular holes, epiretinal membranes, and vit-reomacular traction [32]. The results confirmedthe ability to observe surgically induced chan-ges in retinal contour and macular hole con-figuration. The ability to acquire OCT imagessimultaneously through the microscope over-came a major limitation of a separate externallarge imaging probe by eliminating the need forfrequent pauses during surgery. Commercialsystems are now available with the first beingthe Zeiss RESCAN 700. Increases in imagingspeed combined with improved computationusing graphics processing units (GPUs) haveenabled real-time 3D [72] and 4D [73, 74]intraoperative OCT. This provides improvedfeedback on instrument position. Real-timeadjustments of the OCT focus to maintain par-focality with the surgical microscope at differ-ent axial positions and zoom levels is possible[41]. Improved visualization includes heads-updisplay (HUD) technology that adds OCT visu-alization into the microscope ocular view [45]to project OCT cross-sections [42] onto thesurgical field. Carrasco-Zevallos et al. demon-strated volumetric 4D OCT data for real-timesurgical feedback [73, 75]. Others are examiningdisplaying images on virtual reality (VR) plat-forms and gradually OCT has been added toseveral robotic systems as reported in the fol-lowing section.

ROBOTIC SYSTEMSFOR VITREORETINAL PROCEDURES

To address the host of complications with vit-reoretinal surgery the literature presents severaltypes of robotic systems with an array of fea-tures offering surgical advantages. These roboticsystems fall into four categories distinguishedby their interaction with the surgeon: (1)handheld, (2) telemanipulated, (3) hand-on-hand, and (4) magnetically controlled systems.

Handheld Systems for VitreoretinalProcedures

Handheld robotic surgical tools have beenexplored to address the challenges of physio-logic tremor and force perception with minimaldisruption to the surgical workflow. Oneexample of a handheld robotic surgical device isMicron [7, 76]. Micron is a vitreoretinal surgicaltool designed to sense a surgeon’s tremor anddistinguish those movements from intentionalmotion. It leverages the effects of constructiveand destructive interaction of wave signals tofilter the user’s tremor from the tool tip. Thedevice senses the user’s movements and iden-tifies tremor as any input signal within the8–12 Hz frequency band as determined else-where [5]. To stabilize the surgical tool, piezo-electric actuators direct Micron’s tool tip in adirection opposite and equal in magnitude tothe tremor. Becker et al. [76] (Fig. 1i) improvedon the target acquisition of Micron by addingimage guidance. Two cameras were attacheddirectly to a surgical microscope as a stereo pairfor registering the tool tip’s location and tomeasure the tool’s lateral displacement relativeto target vessels. The displacement data is usedas an additional feedback signal in combinationwith the user’s movements to achieve 63%success in experimental vessel cannulation asshown in Fig. 1ii.

Force sensing was introduced by Gonencet al. [77] using fiber Bragg grating (FBG) strainsensors to enable force sensing at the tool tipfollowing the design from Iordachita et al.’s [78]vitreoretinal tool with a 0.25 mN resolution(5.6 9 10-5 lb). The sensors are located at the

2118 Adv Ther (2021) 38:2114–2129

tool’s tip to isolate retinal forces from the scle-rotomy interaction forces, thereby inhibitingthe user from imposing damaging forces on theretina. Yang et al. [79] optimized the Micron’sdesign to allow six DOFs with a 4-mm-diameterhemispherical workspace by using a parallelactuator architecture offering more robust tre-mor control. Yang et al. [80] used the six-DOFMicron to demonstrate the advantage of usingtremor stabilization in acquiring clear B-modeand C-mode OCT image acquisition and pre-sented a precursor of a clinical tool capable oftremor filtration paired with the visual feedbackcapabilities of OCT.

The Integrated Robotic Intraocular Snake orIRIS, developed by He et al. [25], is a roboticsurgical tool prototype offering surgeonsintraocular dexterity that is meant to be ahandheld device or a mountable attachment toa robotic platform. IRIS was designed to matchthe sizing of 20-gauge ophthalmic surgical toolswith a 0.9 mm outer diameter. The continuumsegment of the IRIS is 10 mm long and has tworotational DOFs each with ± 45� of bending.The linear actuators of the IRIS exhibited largebacklash and low actuation resolution whichlimited the realizable precision of the finaldesign.

Telemanipulation Robotic Systemsfor Vitreoretinal Procedures

Wei et al. [12, 22] presented a multiplatformrobotic system in Fig. 2 that can manipulate theeyeball and offer intraocular dexterity via abending continuum robot capable of deployingmicrostents or grippers. The system allows for asoftware-controlled remote center of motion(RCM). The robotic arms of this system havebeen demonstrated to enable deployment ofmicrostents in chorioallantoic chick mem-branes [24] and were integrated with OCT forcontrol feedback [20] (Fig. 3).

Yu et al. [19] developed surgical forcepsshown in Fig. 4 integrated with a B-mode for-ward-imaging OCT probe enabling real-timeintraocular imaging to improve accuracy formembrane peeling procedures. The forceps weremade with a 25-gauge stainless steel (SS) tubewithin a 23-gauge SS tube. The outer tube slidesalong the 25-gauge tube forcing the openingand closing of the forceps. The group showedthat integration of the custom OCT forceps withthe robot manipulator improved accuracy andreduced the number of attempts needed toaccomplish a membrane peeling procedure.Their results also emphasized the importance of

Fig. 1 i An active surgical tool, Micron, that senses a user’stremor during manual microsurgeries and cancels theeffects of tremor on tool tip trajectory using piezoelectricactuators for procedures such as retinal vein cannulation. iiThe improvement of tool tip trajectory during manual

manipulation with the inclusion of visual feedback toMicron (Figures reproduced with permission from Beckeret al. [76])

Adv Ther (2021) 38:2114–2129 2119

proximity of the OCT image monitor to thesurgeon to minimize head and eye movementsof the user.

Nasseri et al. developed a six-DOF miniaturerobot [81] (Fig. 5). This robot creates linear androtational motion using two parallel prismaticjoints. There are two advantages of such a par-allel mechanism. First the overall stiffness isgreater than what would be possible with seri-ally linked actuators. The second advantage is

the increased DOFs enabled with two separateactuators. This six-DOF robot creates a highlydexterous system eliminating a surgeon’s tre-mor input and minimizing the effect of userfatigue; however, challenges associated withintraocular maneuverability are not addressed.

The Preceyes Surgical Robotic System wasdeveloped for microintraocular procedures likeretinal vein cannulation and internal limitingmembrane peeling. The Preceyes system has amotion controller that the surgeon uses tocommand surgical tool tip position. The surgi-cal tool is attached to a parallelogram manipu-lator that enables operation around an RCM. Bysetting a virtual point, at the sclerotomy,around which a tool will rotate providesadvantages for the user. First, minimized inter-action forces between the surgical tool andsclerotomy mitigate any scleral trauma; second,the orientation of the orbit remains unaffected,which maintains line of site to the surgeon. Thegroup has also integrated the system withexternal OCT imaging to establish tool tipboundaries aiding the user in tool manipulationand preventing inadvertent retinal contact orpuncture [82].

Fig. 2 A two-arm parallel robot used for vitreoretinal operations that allow eye maneuvering and intraocular dexterity(Figure courtesy of Nabil Simaan)

Fig. 3 A nine-DOF robot with parallel actuation platformcarrying a stenting robot capable of maneuvering withprecision better than 5 lm (Photo courtesy of NabilSimaan)

2120 Adv Ther (2021) 38:2114–2129

Gijbels et al. [83] developed a telemanipu-lated robotic system to aid in retinal vein can-nulation and epiretinal membrane peeling andachieved successful in vivo human retinal veincannulation [84]. By enabling axial translationas in Gijbels et al. [83], the size of toolingaround the eye was minimized and the robotworkspace for maneuvering around the micro-scope viewing cone was maximized. Wilsonet al. [85] also developed a unique telemanipu-lated intraocular robotic interventional surgicalsystem (IRISS) with two manipulators thatmount and travel on semicircular tracks. The

tracks can be independently positioned withtwo separate actuators to allow six DOFs ofsurgical tool manipulation. Each tool is kine-matically constrained to a fixed RCM defined bythe device geometry. The IRISS was tested oncadaver porcine eyes to demonstrate retinalvein cannulation and for cataract extraction.The group also tested the feasibility of usingOCT for calibrating the RCM point and con-cluded that RCM alignment using visible reddot lasers may introduce deviations too large forfull autonomy.

Del Giudice et al. [86, 87] developed con-tinuum robots for multiscale motion (CREM)demonstrating a novel concept for teleoperatedrobot actuation for surgeries requiring micro-scale motion like microvascular reconstructionand image-based (OCT) diagnosis. The CREMrobot is capable of maneuvering tools withinboth macro- and micro-workspaces with apositional resolution of 1 lm. It was shown that3D OCT images may be obtained by using therobot’s micromotion capability while carrying aB-mode OCT probe, which was an adaptationfrom Shen et al. [88]. In addition to validating3D OCT on a cadaveric porcine retina, closed-loop control and OCT-guided visual servoing atthe micromotion scale was also demonstratedfor targeting a needle into a microchannel.While this system was not miniaturized tooperate within the eye, the same design conceptmay be used for high-precision and low-cost

Fig. 4 OCT-forceps with OCT fiber embedded in the 25-gauge stainless steel tube (SST). External actuation causes the23-gauge SST to slide axially on the 25-gauge SST causing opening–closing of the forceps (Photo courtesy of Karen Joos)

Fig. 5 A hybrid parallel-serial surgical cooperative robotcapable of microscale motion using piezo actuators(Figure reproduced with permission from Nasseri et al.[81])

Adv Ther (2021) 38:2114–2129 2121

robotic devices for manipulating needles withinthe eye with OCT feedback.

Hand-on-Hand Robotic Systemsfor Vitreoretinal Procedures

By minimizing positioning error of a tool tipcaused by human tremor, some active surgicaltools enable microsurgeries that are impossiblewith traditional surgical tools. Maneuveringhandheld robotic tools for microsurgeries stillrequires a tremendous level of skill, however, asthe level of tremor filtration is limited by thestroke magnitude of the device’s actuators. Liketelemanipulated robots, hand-on-hand robotsoffer a greater advantage of tremor filtration byleveraging the mechanical stiffness of roboticsystems to drive surgical tools in tandem withthe surgeon.

Hand-on-hand robotic systems allow thesurgeon to drive a tool mounted on a roboticplatform using force input commands. Thisapproach has several advantages in terms ofreduced cost and ease of clinical deployment. Inaddition, the robot can be used for tremor fil-tering, for position recall, and for reducingsurgeon fatigue since the robot can hold the

tool at a fixed position even if the surgeon letsgo of it.

The Steady-Hand Robot [10] and Steady-Hand Robot 2 [89], shown in Fig. 6, weredeveloped to augment a surgeon’s capabilitieswith retinal and other microsurgeries in mind.The Steady-Hand is a cooperative robotic sys-tem, where the surgeon and a robotic actuatorsimultaneously control a surgical tool. The sur-geon manipulates surgical tools in the samefashion as traditional tools with the robot con-troller reading force signals from the surgeon’shand movements to drive the robot. The robotis capable of producing smooth, natural motionprofiles that a surgeon would typically use dur-ing retinal procedures while eliminating theextraneous tool movements that result fromtremor.

The first realization of the Steady-Hand fromTaylor et al. [10] improved success of needleinsertion into a hole 150 lm in diameter by36% [90] when compared to manual needleinsertion. Balicki et al. [18] used a custom25-gauge surgical pick with integrated OCT forepiretinal membrane peeling. With the OCTsurgical pick providing visual feedback, theSteady-Hand was able to maintain a specifieddistance of the surgical tool tip from retinal

Fig. 6 i An early iteration of a cooperative surgical robot,the Steady-Hand Robot with robotic platform and surgicaltool attached to a six-DOF force sensor for robot control(Photo courtesy of Russell H. Taylor and Iulian I.Iordachita). ii An iteration of the Steady-Hand Robot,

the Steady-Hand Robot 2, or Eye Robot 2 (ER2). (Fig-ure reproduced with permission from Uneri et al. [10])

2122 Adv Ther (2021) 38:2114–2129

tissue to within 10 lm of a desired 150 lm. TheOCT imaging enabled identification of struc-tures beyond surface layers as targets that can beused to guide tool puncturing tasks while lim-iting puncture depths. Uneri et al. [89] evolvedthe Steady-Hand by including a force sensorattached to the surgical tool. The additionalsensor provides applied tool forces as feedbackdata to the robot controller to limit maximumforces applied to intraocular tissue. The forcefeedback data aids in guiding surgeons to avoidunintended destructive contact and, like theOCT feedback, is used to maintain tool posi-tioning with respect to intraocular anatomy.The combined inputs from the OCT imagingand force sensor optimize tool trajectory, forinstance, while maintaining tool angle during a

peeling motion that minimizes resistance tolimit membrane tearing.

Magnetically Controlled Robot Systems

Finally, other approaches using magneticallycontrolled microrobots have been explored overthe past decade. These systems utilize anextraocular magnetic field to control roboticmicrocapsules within the eye for procedures likeretinal vein cannulation and localized drugdelivery using drug-eluting microcapsules.Kummer et al. [15] used a magnetic field systemcalled the OctoMag (Fig. 7) to guide a micro-capsule robot in five DOFs, i.e., three degrees ofpositional control and two orientationaldegrees. One of the advantages of magneticsystems is achieving high levels of intraoculardexterity and maneuverability without physicalattachment to the extraocular space [15]. Min-imizing attachments between the extraocularand intraocular space eliminates the eyemanipulability constraints imposed by parsplana sclerotomy surgical tools and maximizesthe degrees of manipulation available for theline of site of intraocular anatomy. Theseadvantages, however, come at the expense ofvery complex magnetic field generators thatencompass a large portion of the space aroundthe patient’s head.

Charreyron et al. [16, 17] used the OctoMagmagnetic field system to drive a magnetic tipmicrocannula for delivery of gene therapyinjections to subretinal tissue. The groupdeveloped semiautonomous control that auto-matically aligns the tool magnetic field to keepthe tool tip perpendicular to the retinal surfaceat a target site identified by the surgeon. Theuser, while following tool manipulationthrough the microscope, determines when thetool tip is optimally placed for injection. Mag-netic microcannulas maintain the advantagesof intraocular dexterity that characterizemicrocapsule robots by relying solely on themagnetic field for actuation. These magneticmanipulators also offer a potential safetyadvantage over traditional rigid surgical toolsbecause of their limited rigidity and limitationsof achievable forces. The group explored the

Fig. 7 The extraocular magnetic field generating system,OctoMag, capable of guiding magnetic drug-elutingmicrocapsules and magnetic tip microcannula in fiveDOFs, i.e., three degrees of positional control and twoorientational degrees (Figure courtesy of Bradley Nelsonand MagnebotiX AG, Zurich, Switzerland)

Adv Ther (2021) 38:2114–2129 2123

feasibility of autonomous control and alsoexplored OCT imaging for improved tool tiptracking. Their system exhibits 11 degrees ofangular error of the magnetic field in a worst-case scenario which translates to 4.2 mm ofdisplacement of a 21-mm-long cannula. For fullautonomous control to be clinically realizable,precision of magnetic field alignment will benecessary

DISCUSSION

Vitreoretinal surgical techniques and availableprocedures are in a transitional state due to thecontributions of advanced visualization tech-niques and the development of robotic surgicaldevices. The future of vitreoretinal surgery is thepossible realization of autonomy for an array ofprocedures available today, but more impor-tantly, enabling procedures that are not cur-rently available because of human physiologicallimitations. For instance, gene therapy injec-tions require the utmost precision for targetacquisition. Magnetic field generators guidemagnetic drug-eluting microrobots enablingintraocular drug injections. Magnetic intraocu-lar robots eliminate the pars plana sclerotomymanipulation constraints but require a largevolume of the workspace surrounding thepatient’s head. An alternative approach for tar-geting is OCT imaging which delivers high-definition images necessary for intraocularnavigation. When OCT imaging is paired withrobotic platforms as a feedback modality, thecombined system can drive tools to specificretinal locations with improved accuracy andreduced dependence upon human surgicalskills.

Some of the robotic systems mentioned arealready in a developmental stage where auton-omy is possible. The Steady-Hand robot, forinstance, demonstrated autonomous manipu-lation of a needle inserted into a 150–250 lmhole, improving success of insertion by anaverage of 31.8% compared to handheld inser-tions. With added OCT imaging, performingvitreoretinal tasks expands further to assist inmanipulation of semitransparent membranesand target subsurface tissue. Depending solely

on OCT visual feedback, the robot controllercan bypass the force input from a user to drivesurgical tools to locations identified with theOCT. By utilizing distance measurement capa-bilities of OCT or force guidance with FBGintegrated tool tips, the likelihood of tissuedamaging contact is reduced.

With a system like CREM, tasks requiringultra-precision and autonomous interventionare possible with miniaturization of the tech-nology. Utilizing equilibrium modulation as anactuation technique enables robotics in surgeryto carry out microscale tasks with much finerpositional adjustments than other robots. Fur-ther, enabling these micromanipulation tasksdoes not sacrifice the capabilities in the macro-workspace enabling a greater number of surgicaltasks.

Although surgical robots have shown theircapabilities in advancing vitreoretinal surgery,they are not without limitations. DevelopingOCT-guided robotic tools that do not disruptthe clinical workflow requires hardware capableof high sampling frequencies allowing forimproved OCT image quality via filtering andmultiframe averaging techniques. Registrationof the OCT probe image frame to the robotframe is challenging—especially for systemsusing an external OCT. Stabilization of therobotic tool relative to the patient head (or useof active eye motion tracking) are key toenhancing safety. Finally, the ability to achievefast and safe tool retraction in case of involun-tary ocular movements or in case of a clinicalemergency will be paramount to safe clinicaldeployment.

CONCLUSIONS

Clinical surgical robotics will likely use tech-nologies like OCT and tool tip force measure-ments to enhance the surgeon’s perception andaccuracy. These robotic systems will includepowerful control computers, particularly thoseusing OCT, with calibration methods and con-trol algorithms accounting for safe anatomicalmovements during procedures. The future ofvitreoretinal surgery may include some of therobotic systems or implementations of

2124 Adv Ther (2021) 38:2114–2129

technology introduced in the development ofthe robots discussed in this review.

This review article is based on previouslyconducted studies and does not contain anynew studies with human participants or animalsperformed by any of the authors.

ACKNOWLEDGEMENTS

Funding. This work was supported in part bythe National Institute of Health National EyeInstitute (NEI/NIH) grant 1R01EY028133 (KMJ,NS), in part by The National Science Foundationgrant CMMI-1537659 (NS, KMJ), in part by theJoseph Ellis Family and William Black ResearchFunds (KMJ), in part by the UnrestrictedDepartmental Grant to the Vanderbilt EyeInstitute from Research to Prevent Blindness,Inc., NY (KMJ). No Rapid Service Fee wasreceived by the journal for the publication ofthis article.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Disclosures. Elan Ahronovich declares thathe has no conflict of interest. Nabil Simaan andKaren Joos have received funding from NEI/NIHand NSF.

Compliance with Ethics Guidelines. Thisreview article is based on previously conductedstudies and does not contain any new studieswith human participants or animals performedby any of the authors.

Data Availability. Data sharing is notapplicable to this article as no datasets weregenerated or analyzed during this review article.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,

distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commonslicence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

REFERENCES

1. Machemer R. Vitrectomy, a pars plana approach.Trans Am Acad Ophthalmol. 1971;75:813–20.

2. Jagtap AD, Riviere CN. Applied force during vitre-oretinal microsurgery with handheld instruments.In: The 26th annual international conference of theIEEE engineering in medicine and biology society,vol. 1. IEEE; 2004. pp. 2771–2773.

3. Jensen P, Gupta P, De Juan E. Quantification ofmicrosurgical tactile perception. In: Proceedings ofthe first joint BMES/EMBS conference. 1999 IEEEengineering in medicine and biology 21st annualconference and the 1999 annual fall meeting of thebiomedical engineering society, vol. 2. IEEE; 1999.p. 839.

4. Wilkins JR, Puliafito CA, Hee MR, et al. Character-ization of epiretinal membranes using opticalcoherence tomography. Ophthalmology.1996;103(12):2142–51.

5. Riviere CN, Rader RS, Khosla PK. Characteristics ofhand motion of eye surgeons. In: Proceedings of the19th annual international conference of the IEEEengineering in medicine and biology society ‘Mag-nificent Milestones and Emerging Opportunities inMedical Engineering’ (Cat. No. 97CH36136), vol. 4.IEEE; 1997. pp. 1690–1693.

6. Singh S, Riviere C. Physiological tremor amplitudeduring retinal microsurgery. In: Proceedings of theIEEE 28th annual northeast bioengineering confer-ence (IEEE Cat. No. 02CH37342). IEEE; 2002. pp.171–172.

Adv Ther (2021) 38:2114–2129 2125

7. Riviere CN, Ang WT, Khosla PK. Toward activetremor canceling in handheld microsurgicalinstruments. IEEE Trans Robot Autom. 2003;19(5):793–800.

8. Song C, Gehlbach PL, Kang JU. Active tremor can-cellation by a ‘‘smart’’ handheld vitreoretinalmicrosurgical tool using swept source opticalcoherence tomography. Opt Express. 2012;20(21):23414–21.

9. Cheon GW, Huang Y, Kang JU. Active depth-lock-ing handheld micro-injector based on common-path swept source optical coherence tomography.In: Optical fibers and sensors for medical diagnos-tics and treatment applications XV, vol. 9317.International Society for Optics and Photonics;2015. p. 93170U.

10. Taylor R, Jensen P, Whitcomb L, et al. A steady-hand robotic system for microsurgical augmenta-tion. Int J Robot Res. 1999;18(12):1201–10.

11. Charles S. Dexterity enhancement in microsurgeryusing telemicro-robotics. In: Medicine meets virtualreality II, interactive technology and healthcare:visionary applications for simulation, visualization,robotics; 1994.

12. Wei W, Goldman R, Simaan N, Fine H, Chang S.Design and theoretical evaluation of microsurgicalmanipulators for orbital manipulation andintraocular dexterity. In: Proceedings 2007 IEEEinternational conference on robotics and automa-tion. IEEE; 2007. pp. 3389–3395.

13. Yu H, Shen JH, Joos KM, Simaan N. Design, cali-bration and preliminary testing of a robotic tele-manipulator for OCT guided retinal surgery. In:2013 IEEE international conference on robotics andautomation. IEEE; 2013. pp. 225–231.

14. Meenink T, Naus G, de Smet M, Beelen M, Stein-buch M. Robot assistance for micrometer precisionin vitreoretinal surgery. Investig Ophthalmol VisSci. 2013;54(15):5808–5808.

15. Kummer MP, Abbott JJ, Kratochvil BE, Borer R,Sengul A, Nelson BJ. OctoMag: an electromagneticsystem for 5-DOF wireless micromanipulation. IEEETrans Robot. 2010;26(6):1006–17.

16. Charreyron SL, Zeydan B, Nelson BJ. Shared controlof a magnetic microcatheter for vitreoretinal tar-geted drug delivery. In: ICRA; 2017. pp. 4843–4848.

17. Charreyron SL, Boehler Q, Danun A, Mesot A,Becker M, Nelson BJ. A magnetically navigatedmicrocannula for subretinal injections. In: IEEEtransactions on biomedical engineering. 2020.

18. Balicki M, Han JH, Iordachita I, et al. Single fiberoptical coherence tomography microsurgicalinstruments for computer and robot-assisted retinalsurgery. In: International conference on medicalimage computing and computer-assisted interven-tion. Springer; 2009. pp. 108–115.

19. Yu H, Shen JH, Shah RJ, Simaan N, Joos KM. Eval-uation of microsurgical tasks with OCT-guided and/or robot-assisted ophthalmic forceps. Biomed OptExpress. 2015;6(2):457–72.

20. Yu H, Shen JH, Joos KM, Simaan N. Calibration andintegration of B-mode optical coherence tomogra-phy for assistive control in robotic microsurgery.IEEE ASME Trans Mechatron. 2016;21(6):2613–23.

21. Ikuta K, Kato T, Nagata S. Development andexperimental verification of micro active forceps formicrosurgery. In: MHS’96 proceedings of the sev-enth international symposium on micro machineand human science. IEEE; 1996. pp. 229–234.

22. Wei W, Goldman RE, Fine HF, Chang S, Simaan N.Performance evaluation for multi-arm manipula-tion of hollow suspended organs. IEEE Trans Robot.2008;25(1):147–57.

23. Simaan N, Taylor RH, Handa JT. System andmethod for macro-micro distal dexterity enhance-ment in micro-surgery of the eye. Google Patents;2019. US Patent 10,406,026.

24. Wei W, Popplewell C, Chang S, Fine HF, Simaan N.Enabling technology for microvascular stenting inophthalmic surgery. J Med Devices. 2010;4(1):014503.

25. He X, Van Geirt V, Gehlbach P, Taylor R, IordachitaI. IRIS: integrated robotic intraocular snake. In:2015 IEEE international conference on robotics andautomation (ICRA). IEEE; 2015. pp. 1764–1769.

26. Song J, Gonenc B, Guo J, Iordachita I. Intraocularsnake integrated with the steady-hand eye robot forassisted retinal microsurgery. In: 2017 IEEE inter-national conference on robotics and automation(ICRA). IEEE; 2017. pp. 6724–6729.

27. Dayani PN, Maldonado R, Farsiu S, Toth CA.Intraoperative use of handheld spectral domainoptical coherence tomography imaging in macularsurgery. Retina. 2009;29(10):1457.

28. Binder S, Falkner-Radler CI, Hauger C, Matz H,Glittenberg C. Feasibility of intrasurgical spectral-domain optical coherence tomography. Retina.2011;31(7):1332–6.

29. Hahn P, Migacz J, O’Connell R, Izatt JA, Toth CA.Unprocessed real-time imaging of vitreoretinalsurgical maneuvers using a microscope-integrated

2126 Adv Ther (2021) 38:2114–2129

spectral-domain optical coherence tomographysystem. Graefe’s Arch Clin Exp Ophthalmol.2013;251(1):213–20.

30. Tao YK, Ehlers JP, Toth CA, Izatt JA. Intraoperativespectral domain optical coherence tomography forvitreoretinal surgery. Opt Lett. 2010;35(20):3315–7.

31. Pasricha ND, Shieh C, Carrasco-Zevallos OM, et al.Real-time microscope-integrated OCT to improvevisualization in DSAEK for advanced bullous ker-atopathy. Cornea. 2015;34(12):1606.

32. Hahn P, Migacz J, O’Connell R, et al. Preclinicalevaluation and intraoperative human retinalimaging with a high-resolution microscope-inte-grated spectral domain optical coherence tomog-raphy device. Retina. 2013;33(7):1328.

33. Hahn P, Carrasco-Zevallos O, Cunefare D, et al.Intrasurgical human retinal imaging with manualinstrument tracking using a microscope-integratedspectral-domain optical coherence tomographydevice. Transl Vis Sci Technol. 2015;4(4):1–1.

34. Ehlers JP, Tao YK, Farsiu S, Maldonado R, Izatt JA,Toth CA. Integration of a spectral domain opticalcoherence tomography system into a surgicalmicroscope for intraoperative imaging. InvestigOphthalmol Vis Sci. 2011;52(6):3153–9.

35. Hahn P, Migacz J, O’Connell R, Maldonado RS, IzattJA, Toth CA. The use of optical coherence tomog-raphy in intraoperative ophthalmic imaging. Oph-thalmic Surg Lasers Imaging Retina. 2011;42(4):S85–94.

36. Ehlers J. Intraoperative optical coherence tomog-raphy: past, present, and future. Eye. 2016;30(2):193–201.

37. Ehlers JP, Tao YK, Farsiu S, Maldonado R, Izatt JA,Toth CA. Visualization of real-time intraoperativemaneuvers with a microscope-mounted spectraldomain optical coherence tomography system.Retina. 2013;33(1):232.

38. Grewal DS, Bhullar PK, Pasricha ND, et al. Intraop-erative 4D microscope-integrated optical coherencetomography guided 27-gauge transvitreal reti-nochoroidal biopsy for choroidal melanoma.Retina. 2017;37(4):796.

39. Ehlers JP, McNutt S, Dar S, Tao YK, Srivastava SK.Visualisation of contrast-enhanced intraoperativeoptical coherence tomography with indocyaninegreen. Br J Ophthalmol. 2014;98(11):1588–91.

40. Ehlers JP, Tao YK, Srivastava SK. The value ofintraoperative OCT imaging in vitreoretinal sur-gery. Curr Opin Ophthalmol. 2014;25(3):221.

41. Tao YK, Srivastava SK, Ehlers JP. Microscope-inte-grated intraoperative OCT with electrically tunablefocus and heads-up display for imaging of oph-thalmic surgical maneuvers. Biomed Opt Express.2014;5(6):1877–85.

42. Ehlers JP, Srivastava SK, Feiler D, Noonan AI, RollinsAM, Tao YK. Integrative advances for OCT-guidedophthalmic surgery and intraoperative OCT:microscope integration, surgical instrumentation,and heads-up display surgeon feedback. PLoS One.2014;9(8):e105224.

43. El-Haddad MT, Tao YK. Automated stereo visioninstrument tracking for intraoperative OCT guidedanterior segment ophthalmic surgical maneuvers.Biomed Opt Express. 2015;6(8):3014–31.

44. Ehlers JP, Han J, Petkovsek D, Kaiser PK, Singh RP,Srivastava SK. Membrane peeling-induced retinalalterations on intraoperative OCT in vitreomacularinterface disorders from the PIONEER study.Investig Ophthalmol Vis Sci. 2015;56(12):7324–30.

45. Ehlers JP, Goshe J, Dupps WJ, et al. Determinationof feasibility and utility of microscope-integratedoptical coherence tomography during ophthalmicsurgery: the DISCOVER Study RESCAN Results.JAMA Ophthalmol. 2015;133(10):1124–32.

46. Cost B, Goshe JM, Srivastava S, Ehlers JP. Intraop-erative optical coherence tomography-assistedDescemet membrane endothelial keratoplasty inthe DISCOVER study. Am J Ophthalmol.2015;160(3):430–7.

47. Ehlers JP, Uchida A, Srivastava SK. Intraoperativeoptical coherence tomography-compatible surgicalinstruments for real-time image-guided ophthalmicsurgery. Br J Ophthalmol. 2017;101(10):1306–8.

48. Malone JD, El-Haddad MT, Bozic I, et al. Simulta-neous multimodal ophthalmic imaging usingswept-source spectrally encoded scanning laserophthalmoscopy and optical coherence tomogra-phy. Biomed Opt Express. 2017;8(1):193–206.

49. Lytvynchuk L, Glittenberg C, Binder S. Intraopera-tive spectral domain optical coherence tomogra-phy: technology, applications, and futureperspectives. In: Meyer C, Saxena S, Sadda S, edi-tors. Spectral domain optical coherence tomogra-phy in macular diseases. New Delhi: Springer; 2017.pp. 423–443.

50. Binder S, Falkner-Radler C, Hauger C, Matz H,Glittenberg C. Clinical applications of intrasurgicalSD-optical coherence tomography. Investig Oph-thalmol Vis Sci. 2010;51(13):268–268.

Adv Ther (2021) 38:2114–2129 2127

51. Matz H, Binder S, Glittenberg C, et al. Intraopera-tive applications of OCT in ophthalmic surgery.Biomed Eng. 2012;57(SI-1 Track-P):297–297.

52. Maier MM, Nasseri A, Framme C, Bohnacker S,Becker MD, Heinrich D, et al. Die intraoperativeoptische Koharenztomografie in der Netzhaut-Glaskorper-Chirurgie. Aktuelle Erfahrungen undAusblick auf kunftige Entwicklungsschritte. KlinMonbl Augenheilkd. 2018;235(09):1028–34.

53. Carrasco-Zevallos OM, Viehland C, Keller B, et al.Review of intraoperative optical coherence tomog-raphy: technology and applications. Biomed OptExpress. 2017;8(3):1607–37.

54. Sasahara M, Kiryu J, Yoshimura N. Endoscope-as-sisted transscleral suture fixation to reduce theincidence of intraocular lens dislocation. J CataractRefract Surg. 2005;31(9):1777–80.

55. Tarantola RM, Agarwal A, Lu P, Joos KM. Long-termresults of combined endoscope-assisted pars planavitrectomy and glaucoma tube shunt surgery.Retina. 2011;31(2):275.

56. Olsen TW, Pribila JT. Pars plana vitrectomy withendoscope-guided sutured posterior chamberintraocular lens implantation in children andadults. Am J Ophthalmol. 2011;151(2):287–96.

57. Al Sabti K, Raizada S. Endoscope-assisted pars planavitrectomy in severe ocular trauma. Br J Ophthal-mol. 2012;96(11):1399–403.

58. Maeda M, Watanabe M, Ichikawa K.Goniosynechialysis using an ophthalmic endo-scope and cataract surgery for primary angle-closureglaucoma. J Glaucoma. 2014;23(3):174–8.

59. Kawashima S, Kawashima M, Tsubota K. Endo-scopy-guided vitreoretinal surgery. Expert Rev MedDevices. 2014;11(2):163–8.

60. Francis BA, Kwon J, Fellman R, et al. Endoscopicophthalmic surgery of the anterior segment. SurvOphthalmol. 2014;59(2):217–31.

61. Li J, Quirk BC, Noble PB, Kirk RW, Sampson DD,McLaughlin RA. Flexible needle with integratedoptical coherence tomography probe for imagingduring transbronchial tissue aspiration. J BiomedOpt. 2017;22(10):106002.

62. Iftimia NV, Bouma BE, Pitman MB, Goldberg B,Bressner J, Tearney GJ. A portable, low coherenceinterferometry based instrument for fine needleaspiration biopsy guidance. Rev Sci Instrum.2005;76(6):064301.

63. Li Z, Shen JH, Kozub JA, Prasad R, Lu P, Joos KM.Miniature forward-imaging B-scan optical

coherence tomography probe to guide real-timelaser ablation. Lasers Surg Med. 2014;46(3):193–202.

64. Joos KM, Shen JH. Miniature real-time intraopera-tive forward-imaging optical coherence tomogra-phy probe. Biomed Opt Express. 2013;4(8):1342–50.

65. Joos KM, Shen JH. Preliminary design and evalua-tion of a B-scan OCT-guided needle. Photonics.2014;1:260–266.

66. Ray R, Baranano DE, Fortun JA, et al. Intraoperativemicroscope-mounted spectral domain opticalcoherence tomography for evaluation of retinalanatomy during macular surgery. Ophthalmology.2011;118(11):2212–7.

67. Branchini LA, Gurley K, Duker JS, Reichel E. Use ofhandheld intraoperative spectral-domain opticalcoherence tomography in a variety of vitreoretinaldiseases. Ophthalmic Surg Lasers Imaging Retina.2016;47(1):49–54.

68. Ehlers JP, Dupps WJ, Kaiser PK, et al. The prospec-tive intraoperative and perioperative ophthalmicimaging with optical coherence tomography (PIO-NEER) study: 2-year results. Am J Ophthalmol.2014;158(5):999–1007.

69. De Benito-Llopis L, Mehta JS, Angunawela RI, AngM, Tan DT. Intraoperative anterior segment opticalcoherence tomography: a novel assessment toolduring deep anterior lamellar keratoplasty. Am JOphthalmol. 2014;157(2):334–41.

70. Carrasco-Zevallos O, Keller B, Viehland C, et al. 4Dmicroscope-integrated OCT improves accuracy ofophthalmic surgical maneuvers. In: Ophthalmictechnologies XXVI, vol. 9693. International Societyfor Optics and Photonics; 2016. p. 969306.

71. Todorich B, Shieh C, DeSouza PJ, et al. Impact ofmicroscope-integrated OCT on ophthalmologyresident performance of anterior segment surgicalmaneuvers in model eyes. Investig Ophthalmol VisSci. 2016;57(9):OCT146–53.

72. Wieser W, Draxinger W, Klein T, Karpf S, Pfeiffer T,Huber R. High definition live 3D-OCT in vivo:design and evaluation of a 4D OCT engine with 1GVoxel/s. Biomed Opt Express. 2014;5(9):2963–77.

73. Carrasco-Zevallos O, Keller B, Viehland C, et al. Livevolumetric (4D) visualization and guidance ofin vivo human ophthalmic surgery with intraoper-ative optical coherence tomography. Sci Rep.2016;6:31689.

74. Viehland C, Keller B, Carrasco-Zevallos OM, et al.Enhanced volumetric visualization for real time 4D

2128 Adv Ther (2021) 38:2114–2129

intraoperative ophthalmic swept-source OCT.Biomed Opt Express. 2016;7(5):1815–29.

75. Shen L, Carrasco-Zevallos O, Keller B, et al. Novelmicroscope-integrated stereoscopic heads-up dis-play for intrasurgical optical coherence tomogra-phy. Biomed Opt Express. 2016;7(5):1711–26.

76. Becker BC, Voros S, Lobes LA, Handa JT, Hager GD,Riviere CN. Retinal vessel cannulation with animage-guided handheld robot. In: 2010 Annualinternational conference of the IEEE engineering inmedicine and biology. IEEE; 2010. pp. 5420–5423.

77. Gonenc B, Balicki MA, Handa J, et al. Preliminaryevaluation of a micro-force sensing handheld robotfor vitreoretinal surgery. In: 2012 IEEE/RSJ inter-national conference on intelligent robots and sys-tems. IEEE; 2012. pp. 4125–4130.

78. Iordachita I, Sun Z, Balicki M, et al. A sub-milli-metric, 0.25 mN resolution fully integrated fiber-optic force-sensing tool for retinal microsurgery. IntJ Comput Assist Radiol Surg. 2009;4(4):383–90.

79. Yang S, MacLachlan RA, Riviere CN. Design andanalysis of 6 DOF handheld micromanipulator. In:2012 IEEE international conference on robotics andautomation. IEEE; 2012. pp. 1946–1951.

80. Yang S, Balicki M, MacLachlan RA, et al. Opticalcoherence tomography scanning with a handheldvitreoretinal micromanipulator. In: 2012 Annualinternational conference of the IEEE Engineering inMedicine and Biology Society. IEEE; 2012. pp.948–951.

81. Nasseri MA, Eder M, Eberts D, et al. Kinematics anddynamics analysis of a hybrid parallel-serial micro-manipulator designed for biomedical applications.In: 2013 IEEE/ASME international conference onadvanced intelligent mechatronics. IEEE; 2013. pp.293–299.

82. Maberley DA, Beelen M, Smit J, et al. A comparisonof robotic and manual surgery for internal limitingmembrane peeling. Graefe’s Arch Clin Exp Oph-thalmol. 2020:258(4):773–8.

83. Gijbels A, Vander Poorten EB, Stalmans P, VanBrussel H, Reynaerts D. Design of a teleoperatedrobotic system for retinal surgery. In: 2014 IEEEinternational conference on robotics and automa-tion (ICRA). IEEE; 2014. pp. 2357–2363.

84. Gijbels A, Smits J, Schoevaerdts L, et al. In-humanrobot-assisted retinal vein cannulation, a worldfirst. Ann Biomed Eng. 2018;46(10):1676–85.

85. Wilson JT, Gerber MJ, Prince SW, et al. Intraocularrobotic interventional surgical system (IRISS):mechanical design, evaluation, and master–slavemanipulation. Int J Med Robot Comput Assist Surg.2018;14(1):e1842.

86. Del Giudice G, Wang L, Shen JH, Joos K, Simaan N.Continuum robots for multi-scale motion: micro-scale motion through equilibrium modulation. In:2017 IEEE/RSJ international conference on intelli-gent robots and systems (IROS). IEEE; 2017. pp.2537–2542.

87. Del Giudice G, Orekhov A, Shen J, Joos K, SimaanN. Investigation of micro-motion kinematics ofcontinuum robots for volumetric OCT and OCT-guided visual servoing. IEEE/ASME Trans Mecha-tron. 2020. https://doi.org/10.1109/TMECH.2020.3043438.

88. Shen JH, Kozub J, Prasad R, Joos KM. An intraocularOCT probe. Investig Ophthalmol Vis Sci.2011;52(14):1326–1326.

89. Uneri A, Balicki MA, Handa J, Gehlbach P, TaylorRH, Iordachita I. New steady-hand eye robot withmicro-force sensing for vitreoretinal surgery. In:2010 3rd IEEE RAS and EMBS international confer-ence on biomedical robotics and biomechatronics.IEEE; 2010. pp. 814–819.

90. Kumar R, Goradia TM, Barnes AC, et al. Perfor-mance of robotic augmentation in microsurgery-scale motions. In: International conference onmedical image computing and computer-assistedintervention. Springer; 1999. pp. 1108–1115.

Adv Ther (2021) 38:2114–2129 2129