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First-in-Human Robot-Assisted Subretinal Drug Delivery Under Local Anesthesia

Published:November 14, 2021DOI:https://doi.org/10.1016/j.ajo.2021.11.011

      Purpose

      To report the results of a first-in-human study using a robotic device to assist subretinal drug delivery in patients undergoing vitreoretinal surgery for macular hemorrhage.

      Design

      Double-armed, randomized controlled surgical trial (ClinicalTrials.gov identifier: NCT03052881).

      Methods

      The study was performed at the Oxford Eye Hospital, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom. In total, 12 participants were recruited—6 in the robot-assisted and 6 in the control manual surgery arm according to the prespecified inclusion and exclusion criteria. All subjects presented with acute loss of vision owing to a subfoveal hemorrhage secondary to neovascular age-related macular degeneration. After standard vitrectomy, intraoperative optical coherence tomography–guided subretinal injection of tissue plasminogen activator (TPA) was performed by either robot-assisted or conventional manual technique under local anesthesia. The robotic part of the procedure involved advancement of a cannula through the retina and stabilizing it during foot-controlled injection of up to 100 µL of TPA solution. We assessed surgical success, duration of surgery, adverse events, and tolerability of surgery under local anesthesia.

      Results

      The procedure was well tolerated by all participants and safely performed in all cases. Total duration of surgery, time taken to complete the injection, and retinal microtrauma were similar between the groups and not clinically significant. Subretinal hemorrhage was successfully displaced at 1 month postintervention, except for 1 control subject, and the median gain in visual acuity was similar in both arms.

      Conclusions

      This first-in-human study demonstrates the feasibility and safety of high-precision robot-assisted subretinal drug delivery as part of the surgical management of submacular hemorrhage, simulating its potential future application in gene or cell therapy.
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      References

        • de Smet MD
        • Naus GJL
        • Faridpooya K
        • Mura M.
        Robotic-assisted surgery in ophthalmology.
        Curr Opin Ophthalmol. 2018; 29: 248-253
        • Roizenblatt M
        • Edwards TL
        • Gehlbach PL.
        Robot-assisted vitreoretinal surgery: current perspectives.
        Robot Surg. 2018; 5: 1-11
        • Gerber MJ
        • Pettenkofer M
        • Hubschman J.
        Advanced robotic surgical systems in ophthalmology.
        Eye. 2020; 34: 1554-1562
        • MacLachlan RA
        • Becker BC
        • Tabarés JC
        • Podnar GW
        • Lobes Jr, LA
        • Riviere CN.
        Micron: an actively stabilized handheld tool for microsurgery.
        IEEE Trans Robot. 2011; 28: 195-212
        • Yang S
        • MacLachlan RA
        • Riviere CN.
        Manipulator design and operation of a six-degree-of-freedom handheld tremor-canceling microsurgical instrument.
        IEEE/ASME Trans Mechatron. 2014; 20: 761-772
        • Uneri A
        • Balicki MA
        • Handa J.
        • Gehlbach P
        • Taylor RH
        • Iordachita I.
        New steady-hand eye robot with micro-force sensing for vitreoretinal surgery.
        in: Proceedings of the 2010 3rd IEEE RAS & EMBS International Conference on Biomedical Robotics and Biomechatronics (BioRob). IEEE, 2010: 814-819
        • He X
        • Roppenecker D
        • Gierlach D
        • et al.
        Toward clinically applicable steady-hand eye robot for vitreoretinal surgery.
        in: Proceedings of the ASME 2012 International Mechanical Engineering Congress & Exposition (IMECE2012) 2012: November 9-15, 2012, Houston, Texas American Society of Mechanical Engineers, 2013: 145-153 (Paper no. 88384)
        • Gijbels A
        • Reynaerts D
        • Vander Poorten EB.
        Design of 4-DOF parallelogram-based RCM mechanisms with a translational DOF implemented distal from the end-effector.
        in: Advances on Theory and Practice of Robots and Manipulators: Proceedings of Romansy 2014 XX CISM-IFToMM Symposium on Theory and Practice of Robots and Manipulators. Springer International, 2014: 103-111
        • Meenink HCM
        • Hendrix R
        • Rosielle PCJN
        • Steinbuch M
        • Nijmeijer H
        • de Smet MD.
        A master-slave robot for vitreo-retinal eye surgery.
        in: Proceedings of the EUSPEN International Conference. EUSPEN, 2010: 3-6
        • Meenink T
        • Naus G
        • de Smet MD
        • Beelen M
        • Steinbuch M.
        Robot assistance for micrometer precision in vitreoretinal surgery.
        Invest Ophthalmol Vis Sci. 2013; 54: 5808
        • Wilson JT
        • Gerber MJ
        • Prince SW
        • et al.
        Intraocular robotic interventional surgical system (IRISS): mechanical design, evaluation, and master–slave manipulation.
        Int J Med Robot Computer Assist Surg. 2018; 14: e1842
        • Forslund Jacobsen M
        • Konge L
        • Alberti M
        • la Cour M
        • Park YS
        • Thomsen ASS.
        Robot-assisted vitreoretinal surgery improves surgical accuracy compared with manual surgery: a randomized trial in a simulated setting.
        Retina. 2019; 40: 2091-2098
        • Ueta T
        • Yamaguchi Y
        • Shirakawa Y
        • et al.
        Robot-assisted vitreoretinal surgery: development of a prototype and feasibility studies in an animal model.
        Ophthalmology. 2009; 116: 1538-1543
        • Maberley DAL
        • Beelen M
        • Smit J
        • et al.
        A comparison of robotic and manual surgery for internal limiting membrane peeling.
        Graefes Arch Clin Exp Ophthalmol. 2020; 258: 773-778
        • de Smet MD
        • Meenink TC
        • Janssens T
        • et al.
        Robotic assisted cannulation of occluded retinal veins.
        PLoS One. 2016; 11e0162037
        • Edwards TL
        • Xue K
        • Meenink HCM
        • et al.
        First-in-human study of the safety and viability of intraocular robotic surgery.
        Nat Biomed Eng. 2018; 2: 649-656
        • de Smet MD
        • Stassen JM
        • Meenink TC
        • et al.
        Release of experimental retinal vein occlusions by direct intraluminal injection of ocriplasmin.
        Br J Ophthalmol. 2016; 100: 1742-1746
        • Gijbels A
        • Smits J
        • Schoevaerdts L
        • et al.
        In-human robot-assisted retinal vein cannulation, a world first.
        Ann Biomed Eng. 2018; 46: 1676-1685
        • Russell S
        • Bennett J
        • Wellman JA
        • et al.
        Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial.
        Lancet. 2017; 390: 849-860
        • Xue K
        • Jolly JK
        • Barnard AR
        • et al.
        Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia.
        Nat Med. 2018; 24: 1507-1512
        • Cehajic-Kapetanovic J
        • Xue K
        • Martinez-Fernandez de la Camara C
        • et al.
        Initial results from a first-in-human gene therapy trial on X-linked retinitis pigmentosa caused by mutations in RPGR.
        Nat Med. 2020; 26: 354-359
        • Singh MS
        • Park SS
        • Albini TA
        • et al.
        Retinal stem cell transplantation: balancing safety and potential.
        Prog Retinal Eye Res. 2019; 100779
        • Jones BW
        • Pfeiffer RL
        • Ferrell WD
        • Watt CB
        • Marmor M
        • Marc RE.
        Retinal remodeling in human retinitis pigmentosa.
        Exp Eye Res. 2016; 150: 149-165
        • Pfeiffer RL
        • Marc RE
        • Jones BW.
        Persistent remodeling and neurodegeneration in late-stage retinal degeneration.
        Prog Retin Eye Res. 2019; 26100771
        • Bennett SR
        • Folk JC
        • Blodi CF
        • Klugman F.
        Factors prognostic of visual outcome in patients with subretinal haemorrhage.
        Am J Ophthalmol. 1990; 109: 33-37
        • Toth CA
        • Morse LS
        • Hjelmeland LM
        • Landers III, MB
        Fibrin directs early retinal damage after experimental subretinal haemorrhage.
        Arch Ophthalmol. 1991; 109: 723-729
        • Avery RL
        • Fekrat S
        • Hawkins BS
        • Bressler NM.
        Natural history of subfoveal subretinal hemorrhage in age-related macular degeneration.
        Retina. 1996; 16: 183-189
        • Peyman GA
        • Nelson Jr, NC
        • Alturki W
        • et al.
        Tissue plasminogen activating factor assisted removal of subretinal haemorrhage.
        Ophthalmic Surg. 1991; 22: 575-582
        • Olivier S
        • Chow DR
        • Packo KH
        • MacCumber MW
        • Awh CC.
        Subretinal recombinant tissue plasminogen activator injection and pneumatic displacement of thick submacular hemorrhage in age-related macular degeneration.
        Ophthalmology. 2004; 111: 1201-1208
        • Xue K
        • Groppe M
        • Salvetti AP
        • MacLaren RE.
        Technique of retinal gene therapy: delivery of viral vector into the subretinal space.
        Eye. 2017; 31: 1308-1316
        • Edington M
        • Connolly J
        • Chong NV.
        Pharmacokinetics of intravitreal anti-VEGF drugs in vitrectomized versus non-vitrectomized eyes.
        Expert Opin Drug Metab Toxicol. 2017; 13: 1217-1224
        • Cukras C
        • Wiley HE
        • Jeffrey BG
        • et al.
        Retinal AAV8-RS1 gene therapy for X-linked retinoschisis: initial findings from a phase I/IIa trial by intravitreal delivery.
        Mol Ther. 2018; 26: 2282-2294
        • Maguire AM
        • Simonelli F
        • Pierce EA
        • et al.
        Safety and efficacy of gene transfer for Leber's congenital amaurosis.
        N Engl J Med. 2008; 358: 2240-2248