{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:25:51Z","timestamp":1791951951325,"version":"4.3.4"},"reference-count":51,"publisher":"Springer Science and Business Media LLC","issue":"11","license":[{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T00:00:00Z","timestamp":1758153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Graefes Arch Clin Exp Ophthalmol"],"published-print":{"date-parts":[[2025,11]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Retinal therapeutics has been revolutionized by anti-vascular endothelial growth factor (VEGF) therapies, whereby intravitreal injection is the accepted delivery method. To date, the possibility of direct surgical delivery to the subretinal space or an endovascular approach has yet to be explored. Herein, we investigate the feasibility of a microinvasive approach for anti-VEGF therapies using microneedles as small as 49G in internal diameter.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In vitro microinjections of commercially available anti-VEGF products, including broliucizumab, faricimab, aflibercept, and ranibizumab, were used to measure the consistency of 1\u00b5L droplet formation and needle occlusion thresholds. A validated fresh ex vivo porcine model used to examine microinjections of anti-VEGF solutions with fluorescent microbeads in the subretinal space and intravascular delivery. Spectral domain optical coherence (SD-OCT) imaging and histological retinal wholemounts were used to analyse the drug distribution.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In vitro, we find that of the commercially available formulations of aflibercept, brolucizumab, faricimab and ranibizumab, a 5% aflibercept solution and 2.5% ranibizumab solution can be reliably injected as 1\u00b5L droplets repeatedly through a microneedle. Using a fresh porcine ex vivo closed vitrecomy model, we demonstrate that ranibizumab admixed with fluorescent microbeads, can be reliably injected in ca. 25\u00b5L volumes into the subretinal space and endovascularly, without any risk of needle occlusion. We demonstrate using SD-OCT, retinal whole mounts and immunofluorescent microscopy, that direct retinal anti-VEGF delivery is feasible.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>We conclude that further study is warranted to determine whether such an approach has any advantages over the conventional approach of intravitreal injections in terms of treatment safety, efficacy and durability.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key messages<\/jats:title>\n                    <jats:p>\n                      <jats:bold>\n                        <jats:italic>What is known<\/jats:italic>\n                      <\/jats:bold>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>Injections of anti-vascular endothelial growth factor (VEGF) therapies in the intravitreal 23 space are widely used to treat retinal diseases, requiring repeated and frequent 24 injections due to the limited durability of these therapies.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>New approaches to address this include implantable reservoir systems to reduce the 26 need for repeated injections.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                      <jats:bold>\n                        <jats:italic>What is new<\/jats:italic>\n                      <\/jats:bold>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>The feasibility of a microinvasive approach to deliver anti-VEGF therapies is explored 30 using microneedles as small as 49G.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>Low concentrations of the commercially available anti-VEGF products ranibizumab and 32 aflibercept can be injected into the subretinal space and intravascularly in an ex vivo 33 porcine model.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>These results warrant further study to understand if such approaches affect efficacy and 35 durability of anti-VEGF therapies.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00417-025-06960-0","type":"journal-article","created":{"date-parts":[[2025,9,18]],"date-time":"2025-09-18T08:02:00Z","timestamp":1758182520000},"page":"3131-3145","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Investigating the feasibility of selective anti-VEGF delivery to the retina using a microinvasive approach"],"prefix":"10.1007","volume":"263","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3562-8055","authenticated-orcid":false,"given":"Jared","family":"Ching","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mizuho","family":"Arai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayu","family":"Ooba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Misa","family":"Miyazato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yumei","family":"Kobayashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shin","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohei","family":"Kitahata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuya","family":"Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maiko","family":"Maruyama-Inoue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuaki","family":"Kadonosono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,9,18]]},"reference":[{"key":"6960_CR1","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1007\/BF00941723","volume":"235","author":"T Ishibashi","year":"1997","unstructured":"Ishibashi T, Hata Y, Yoshikawa H, Nakagawa K, Sueishi K, Inomata H (1997) Expression of vascular endothelial growth factor in experimental choroidal neovascularization. Graefes Arch Clin Exp Ophthalmol 235:159\u2013167. https:\/\/doi.org\/10.1007\/BF00941723","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"key":"6960_CR2","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1016\/j.ophtha.2012.07.038","volume":"120","author":"JW Miller","year":"2013","unstructured":"Miller JW, Le Couter J, Strauss EC, Ferrara N (2013) Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology 120:106\u2013114. https:\/\/doi.org\/10.1016\/j.ophtha.2012.07.038","journal-title":"Ophthalmology"},{"key":"6960_CR3","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1634\/theoncologist.2008-0213","volume":"14","author":"HI Hurwitz","year":"2009","unstructured":"Hurwitz HI, Yi J, Ince W, Novotny WF, Rosen O (2009) The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist 14:22\u201328. https:\/\/doi.org\/10.1634\/theoncologist.2008-0213","journal-title":"Oncologist"},{"key":"6960_CR4","doi-asserted-by":"publisher","first-page":"331","DOI":"10.3928\/1542-8877-20050701-14","volume":"36","author":"PJ Rosenfeld","year":"2005","unstructured":"Rosenfeld PJ, Moshfeghi AA, Puliafito CA (2005) Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 36:331\u2013335","journal-title":"Ophthalmic Surg Lasers Imaging"},{"key":"6960_CR5","doi-asserted-by":"publisher","first-page":"2537","DOI":"10.1016\/j.ophtha.2012.09.006","volume":"119","author":"JS Heier","year":"2012","unstructured":"Heier JS, Brown DM, Chong V, Korobelnik JF, Kaiser PK, Nguyen QD, Kirchhof B, Ho A, Ogura Y, Yancopoulos GD, Stahl N, Vitti R, Berliner AJ, Soo Y, Anderesi M, Groetzbach G, Sommerauer B, Sandbrink R, Simader C, Schmidt-Erfurth U, Groups VVS (2012) Intravitreal aflibercept (VEGF trap-eye) in wet age-related macular degeneration. Ophthalmology 119:2537\u20132548. https:\/\/doi.org\/10.1016\/j.ophtha.2012.09.006","journal-title":"Ophthalmology"},{"key":"6960_CR6","doi-asserted-by":"publisher","first-page":"1124","DOI":"10.1016\/j.ophtha.2010.02.022","volume":"117","author":"DM Brown","year":"2010","unstructured":"Brown DM, Campochiaro PA, Singh RP, Li Z, Gray S, Saroj N, Rundle AC, Rubio RG, Murahashi WY, Investigators C (2010) Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 117:1124\u20131133e1121. https:\/\/doi.org\/10.1016\/j.ophtha.2010.02.022","journal-title":"Ophthalmology"},{"key":"6960_CR7","doi-asserted-by":"publisher","first-page":"1351","DOI":"10.1016\/j.ophtha.2016.02.022","volume":"123","author":"JA Wells","year":"2016","unstructured":"Wells JA, Glassman AR, Ayala AR, Jampol LM, Bressler NM, Bressler SB, Brucker AJ, Ferris FL, Hampton GR, Jhaveri C, Melia M, Beck RW, Network DRCR (2016) Aflibercept, bevacizumab, or Ranibizumab for diabetic macular edema: Two-Year results from a comparative effectiveness randomized clinical trial. Ophthalmology 123:1351\u20131359. https:\/\/doi.org\/10.1016\/j.ophtha.2016.02.022","journal-title":"Ophthalmology"},{"key":"6960_CR8","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.ophtha.2019.04.017","volume":"127","author":"PU Dugel","year":"2020","unstructured":"Dugel PU, Koh A, Ogura Y, Jaffe GJ, Schmidt-Erfurth U, Brown DM, Gomes AV, Warburton J, Weichselberger A, Holz FG, Investigators HHS (2020) HAWK and HARRIER: phase 3, multicenter, randomized, double-masked trials of brolucizumab for neovascular age-related macular degeneration. Ophthalmology 127:72\u201384. https:\/\/doi.org\/10.1016\/j.ophtha.2019.04.017","journal-title":"Ophthalmology"},{"key":"6960_CR9","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.ophtha.2020.06.028","volume":"128","author":"PU Dugel","year":"2021","unstructured":"Dugel PU, Singh RP, Koh A, Ogura Y, Weissgerber G, Gedif K, Jaffe GJ, Tadayoni R, Schmidt-Erfurth U, Holz FG (2021) HAWK and HARRIER: Ninety-Six-Week outcomes from the phase 3 trials of Brolucizumab for neovascular Age-Related macular degeneration. Ophthalmology 128:89\u201399. https:\/\/doi.org\/10.1016\/j.ophtha.2020.06.028","journal-title":"Ophthalmology"},{"key":"6960_CR10","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1016\/S0140-6736(22)00010-1","volume":"399","author":"JS Heier","year":"2022","unstructured":"Heier JS, Khanani AM, Quezada Ruiz C, Basu K, Ferrone PJ, Brittain C, Figueroa MS, Lin H, Holz FG, Patel V, Lai TYY, Silverman D, Regillo C, Swaminathan B, Viola F, Cheung CMG, Wong TY, Investigators TaL (2022) Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials. Lancet 399:729\u2013740. https:\/\/doi.org\/10.1016\/S0140-6736(22)00010-1","journal-title":"Lancet"},{"key":"6960_CR11","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1016\/j.ajo.2022.01.004","volume":"238","author":"DM Brown","year":"2022","unstructured":"Brown DM, Emanuelli A, Bandello F, Barranco JJE, Figueira J, Souied E, Wolf S, Gupta V, Ngah NF, Liew G, Tuli R, Tadayoni R, Dhoot D, Wang L, Bouillaud E, Wang Y, Kovacic L, Guerard N, Garweg JG (2022) KESTREL and KITE: 52-week results from two phase III pivotal trials of brolucizumab for diabetic macular edema. Am J Ophthalmol 238:157\u2013172. https:\/\/doi.org\/10.1016\/j.ajo.2022.01.004","journal-title":"Am J Ophthalmol"},{"key":"6960_CR12","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1016\/j.ajo.2010.08.039","volume":"151","author":"AE Green-Simms","year":"2011","unstructured":"Green-Simms AE, Ekdawi NS, Bakri SJ (2011) Survey of intravitreal injection techniques among retinal specialists in the United States. Am J Ophthalmol 151:329\u2013332. https:\/\/doi.org\/10.1016\/j.ajo.2010.08.039","journal-title":"Am J Ophthalmol"},{"key":"6960_CR13","doi-asserted-by":"publisher","first-page":"366","DOI":"10.3109\/09273948.2013.801988","volume":"21","author":"HA Tufan","year":"2013","unstructured":"Tufan HA, Vural A, Gencer B, Kara S, Arikan S, Yuksel E (2013) Bacterial contamination of needles used for intravitreal injections: comparison between 27-gauge and 30-gauge needles. Ocul Immunol Inflamm 21:366\u2013370. https:\/\/doi.org\/10.3109\/09273948.2013.801988","journal-title":"Ocul Immunol Inflamm"},{"key":"6960_CR14","doi-asserted-by":"publisher","first-page":"947","DOI":"10.1016\/j.ophtha.2018.01.038","volume":"125","author":"H Sasajima","year":"2018","unstructured":"Sasajima H, Tsuboi K, Ono H, Murotani K, Kamei M (2018) A randomized trial of a short 34-Gauge needle for intravitreal injections. Ophthalmology 125:947\u2013948. https:\/\/doi.org\/10.1016\/j.ophtha.2018.01.038","journal-title":"Ophthalmology"},{"key":"6960_CR15","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1007\/s40123-023-00879-7","volume":"13","author":"ETS Butler","year":"2024","unstructured":"Butler ETS, Bjerager J, Eriksen NS, Hajari JN, Schneider M, Faber C, Subhi Y (2024) Effect of needle gauge size on pain during intravitreal anti-VEGF injection: a systematic review and network meta-analysis. Ophthalmol Ther 13:801\u2013817. https:\/\/doi.org\/10.1007\/s40123-023-00879-7","journal-title":"Ophthalmol Ther"},{"key":"6960_CR16","doi-asserted-by":"publisher","first-page":"e018289","DOI":"10.1136\/bmjopen-2017-018289","volume":"7","author":"W Hollingworth","year":"2017","unstructured":"Hollingworth W, Jones T, Reeves BC, Peto T (2017) A longitudinal study to assess the frequency and cost of antivascular endothelial therapy, and inequalities in access, in England between 2005 and 2015. BMJ Open 7:e018289. https:\/\/doi.org\/10.1136\/bmjopen-2017-018289","journal-title":"BMJ Open"},{"key":"6960_CR17","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1080\/10717544.2022.2069301","volume":"29","author":"SV Ranade","year":"2022","unstructured":"Ranade SV, Wieland MR, Tam T, Rea JC, Horvath J, Hieb AR, Jia W, Grace L, Barteselli G, Stewart JM (2022) The port delivery system with ranibizumab: a new paradigm for long-acting retinal drug delivery. Drug Deliv 29:1326\u20131334. https:\/\/doi.org\/10.1080\/10717544.2022.2069301","journal-title":"Drug Deliv"},{"key":"6960_CR18","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1186\/s40942-023-00446-z","volume":"9","author":"A Sharma","year":"2023","unstructured":"Sharma A, Khanani AM, Parachuri N, Kumar N, Bandello F, Kuppermann BD (2023) Port delivery system with Ranibizumab (Susvimo) recall- what does it mean to the retina specialists. Int J Retina Vitreous 9:6. https:\/\/doi.org\/10.1186\/s40942-023-00446-z","journal-title":"Int J Retina Vitreous"},{"key":"6960_CR19","doi-asserted-by":"publisher","first-page":"5790","DOI":"10.1167\/iovs.11-7327","volume":"52","author":"K Kadonosono","year":"2011","unstructured":"Kadonosono K, Arakawa A, Yamane S, Uchio E, Yanagi Y (2011) An experimental study of retinal endovascular surgery with a microfabricated needle. Invest Ophthalmol Vis Sci 52:5790\u20135793. https:\/\/doi.org\/10.1167\/iovs.11-7327","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"6960_CR20","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1001\/jamaophthalmol.2013.2585","volume":"131","author":"K Kadonosono","year":"2013","unstructured":"Kadonosono K, Yamane S, Arakawa A, Inoue M, Yamakawa T, Uchio E, Yanagi Y, Amano S (2013) Endovascular cannulation with a microneedle for central retinal vein occlusion. JAMA Ophthalmol 131:783\u2013786. https:\/\/doi.org\/10.1001\/jamaophthalmol.2013.2585","journal-title":"JAMA Ophthalmol"},{"key":"6960_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-19747-7","author":"K Kadonosono","year":"2018","unstructured":"Kadonosono K, Yamane S, Inoue M, Yamakawa T, Uchio E (2018) Intra-retinal arterial cannulation using a microneedle for central retinal artery occlusion. Sci Rep. https:\/\/doi.org\/10.1038\/s41598-018-19747-7","journal-title":"Sci Rep"},{"key":"6960_CR22","first-page":"1867","volume":"30","author":"J Sebag","year":"1989","unstructured":"Sebag J, Balazs EA (1989) Morphology and ultrastructure of human vitreous fibers. Invest Ophthalmol Vis Sci 30:1867\u20131871","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"6960_CR23","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1002\/cne.20516","volume":"486","author":"M Garc\u00e1","year":"2005","unstructured":"Garc\u00e1 M, Ruiz-Ederra J, Hern\u00e1ndez-Barb\u00e1chano H, Vecino E (2005) Topography of pig retinal ganglion cells. J Comp Neurol 486:361\u2013372. https:\/\/doi.org\/10.1002\/cne.20516","journal-title":"J Comp Neurol"},{"key":"6960_CR24","doi-asserted-by":"publisher","DOI":"10.1063\/5.0201626","volume":"8","author":"CM Lewis","year":"2024","unstructured":"Lewis CM, Heise CT, Harasimiuk N, Tovey J, Lu JR, Waigh TA (2024) The viscoelasticity of high concentration monoclonal antibodies using particle tracking microrheology. APL Bioeng 8:026105. https:\/\/doi.org\/10.1063\/5.0201626","journal-title":"APL Bioeng"},{"key":"6960_CR25","doi-asserted-by":"publisher","first-page":"709","DOI":"10.1136\/bjo.58.8.709","volume":"58","author":"N Drasdo","year":"1974","unstructured":"Drasdo N, Fowler CW (1974) Non-linear projection of the retinal image in a wide-angle schematic eye. Br J Ophthalmol 58:709\u2013714. https:\/\/doi.org\/10.1136\/bjo.58.8.709","journal-title":"Br J Ophthalmol"},{"key":"6960_CR26","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1080\/07853890600946724","volume":"38","author":"KM Gehrs","year":"2006","unstructured":"Gehrs KM, Anderson DH, Johnson LV, Hageman GS (2006) Age-related macular degeneration\u2013emerging pathogenetic and therapeutic concepts. Ann Med 38:450\u2013471. https:\/\/doi.org\/10.1080\/07853890600946724","journal-title":"Ann Med"},{"key":"6960_CR27","doi-asserted-by":"publisher","DOI":"10.1016\/j.preteyeres.2020.100862","volume":"80","author":"GB Melo","year":"2021","unstructured":"Melo GB, Cruz NFSD, Emerson GG, Rezende FA, Meyer CH, Uchiyama S, Carpenter J, Shiroma HF, Farah ME, Maia M, Rodrigues EB (2021) Critical analysis of techniques and materials used in devices, syringes, and needles used for intravitreal injections. Prog Retin Eye Res 80:100862. https:\/\/doi.org\/10.1016\/j.preteyeres.2020.100862","journal-title":"Prog Retin Eye Res"},{"key":"6960_CR28","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/nmeth.1993","volume":"9","author":"SB Kodandaramaiah","year":"2012","unstructured":"Kodandaramaiah SB, Franzesi GT, Chow BY, Boyden ES, Forest CR (2012) Automated whole-cell patch-clamp electrophysiology of neurons in vivo. Nat Methods 9:585\u2013587. https:\/\/doi.org\/10.1038\/nmeth.1993","journal-title":"Nat Methods"},{"key":"6960_CR29","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.precisioneng.2016.04.003","volume":"46","author":"MA Stockslager","year":"2016","unstructured":"Stockslager MA, Capocasale CM, Holst GL, Simon MD, Li Y, McGruder DJ, Rousseau EB, Stoy WA, Sulchek T, Forest CR (2016) Optical method for automated measurement of glass micropipette tip geometry. Precis Eng 46:88\u201395. https:\/\/doi.org\/10.1016\/j.precisioneng.2016.04.003","journal-title":"Precis Eng"},{"key":"6960_CR30","doi-asserted-by":"publisher","first-page":"2169440","DOI":"10.1080\/19420862.2023.2169440","volume":"15","author":"J Schmitt","year":"2023","unstructured":"Schmitt J, Razvi A, Grapentin C (2023) Predictive modeling of concentration-dependent viscosity behavior of monoclonal antibody solutions using artificial neural networks. MAbs 15:2169440. https:\/\/doi.org\/10.1080\/19420862.2023.2169440","journal-title":"MAbs"},{"key":"6960_CR31","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1002\/jps.21898","volume":"99","author":"S Yadav","year":"2010","unstructured":"Yadav S, Liu J, Shire SJ, Kalonia DS (2010) Specific interactions in high concentration antibody solutions resulting in high viscosity. J Pharm Sci 99:1152\u20131168. https:\/\/doi.org\/10.1002\/jps.21898","journal-title":"J Pharm Sci"},{"key":"6960_CR32","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1056\/NEJMoa0802268","volume":"358","author":"JW Bainbridge","year":"2008","unstructured":"Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR (2008) Effect of gene therapy on visual function in Leber\u2019s congenital amaurosis. N Engl J Med 358:2231\u20132239. https:\/\/doi.org\/10.1056\/NEJMoa0802268","journal-title":"N Engl J Med"},{"key":"6960_CR33","doi-asserted-by":"publisher","first-page":"1887","DOI":"10.1056\/NEJMoa1414221","volume":"372","author":"JW Bainbridge","year":"2015","unstructured":"Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, Georgiadis A, Mowat FM, Beattie SG, Gardner PJ, Feathers KL, Luong VA, Yzer S, Balaggan K, Viswanathan A, de Ravel TJ, Casteels I, Holder GE, Tyler N, Fitzke FW, Weleber RG, Nardini M, Moore AT, Thompson DA, Petersen-Jones SM, Michaelides M, van den Born LI, Stockman A, Smith AJ, Rubin G, Ali RR (2015) Long-term effect of gene therapy on leber\u2019s congenital amaurosis. N Engl J Med 372:1887\u20131897. https:\/\/doi.org\/10.1056\/NEJMoa1414221","journal-title":"N Engl J Med"},{"key":"6960_CR34","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1186\/s13063-021-05966-3","volume":"23","author":"TL Jackson","year":"2022","unstructured":"Jackson TL, Bunce C, Desai R, Hillenkamp J, Lee CN, Lois N, Peto T, Reeves BC, Steel DH, Edwards RT, van Meurs JC, Wafa H, Wang Y (2022) Vitrectomy, subretinal tissue plasminogen activator and intravitreal gas for submacular haemorrhage secondary to exudative age-related macular degeneration (TIGER): study protocol for a phase 3, pan-European, two-group, non-commercial, active-control, observer-masked, superiority, randomised controlled surgical trial. Trials 23:99. https:\/\/doi.org\/10.1186\/s13063-021-05966-3","journal-title":"Trials"},{"key":"6960_CR35","doi-asserted-by":"publisher","unstructured":"Sugita S, Mandai M, Hirami Y, Takagi S, Maeda T, Fujihara M, Matsuzaki M, Yamamoto M, Iseki K, Hayashi N, Hono A, Fujino S, Koide N, Sakai N, Shibata Y, Terada M, Nishida M, Dohi H, Nomura M, Takahashi M (2020) HLA-Matched allogeneic iPS Cells-Derived RPE transplantation for macular degeneration. J Clin Med 9. https:\/\/doi.org\/10.3390\/jcm9072217","DOI":"10.3390\/jcm9072217"},{"key":"6960_CR36","doi-asserted-by":"publisher","unstructured":"Moshfeghi AA, Rosenfeld PJ, Puliafito CA, Michels S, Marcus EN, Lenchus JD, Venkatraman AS (2006) Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twenty-four-week results of an uncontrolled open-label clinical study. Ophthalmology 113: 2002.e2001-2012 https:\/\/doi.org\/10.1016\/j.ophtha.2006.05.070","DOI":"10.1016\/j.ophtha.2006.05.070"},{"key":"6960_CR37","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1016\/j.preteyeres.2008.11.005","volume":"28","author":"EB Rodrigues","year":"2009","unstructured":"Rodrigues EB, Farah ME, Maia M, Penha FM, Regatieri C, Melo GB, Pinheiro MM, Zanetti CR (2009) Therapeutic monoclonal antibodies in ophthalmology. Prog Retin Eye Res 28:117\u2013144. https:\/\/doi.org\/10.1016\/j.preteyeres.2008.11.005","journal-title":"Prog Retin Eye Res"},{"key":"6960_CR38","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.omtm.2023.02.006","volume":"28","author":"JB Ducloyer","year":"2023","unstructured":"Ducloyer JB, Pichard V, Mevel M, Galy A, Lefevre GM, Brument N, Alvarez-Dorta D, Deniaud D, Mendes-Madeira A, Libeau L, Le Guiner C, Cronin T, Adjali O, Weber M, Le Meur G (2023) Intravitreal air tamponade after AAV2 subretinal injection modifies retinal EGFP distribution. Mol Ther Methods Clin Dev 28:387\u2013393. https:\/\/doi.org\/10.1016\/j.omtm.2023.02.006","journal-title":"Mol Ther Methods Clin Dev"},{"key":"6960_CR39","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1016\/j.survophthal.2015.04.004","volume":"61","author":"D Stanescu-Segall","year":"2016","unstructured":"Stanescu-Segall D, Balta F, Jackson TL (2016) Submacular hemorrhage in neovascular age-related macular degeneration: a synthesis of the literature. Surv Ophthalmol 61:18\u201332. https:\/\/doi.org\/10.1016\/j.survophthal.2015.04.004","journal-title":"Surv Ophthalmol"},{"key":"6960_CR40","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1016\/j.survophthal.2024.05.004","volume":"69","author":"D L\u2019Abbate","year":"2024","unstructured":"L\u2019Abbate D, Prescott K, Geraghty B, Kearns VR, Steel DHW (2024) Biomechanical considerations for optimising subretinal injections. Surv Ophthalmol 69:722\u2013732. https:\/\/doi.org\/10.1016\/j.survophthal.2024.05.004","journal-title":"Surv Ophthalmol"},{"key":"6960_CR41","doi-asserted-by":"publisher","first-page":"1308","DOI":"10.1038\/eye.2017.158","volume":"31","author":"K Xue","year":"2017","unstructured":"Xue K, Groppe M, Salvetti AP, MacLaren RE (2017) Technique of retinal gene therapy: delivery of viral vector into the subretinal space. Eye (Lond) 31:1308\u20131316. https:\/\/doi.org\/10.1038\/eye.2017.158","journal-title":"Eye (Lond)"},{"key":"6960_CR42","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1167\/iovs.65.12.41","volume":"65","author":"IP Seitz","year":"2024","unstructured":"Seitz IP, Peters T, Reichel F, B\u00e4hr A, Auch H, Motlik J, Ardan T, Juhasova J, Nemesh Y, Juh\u00e1s S, Klymiuk N, Fischer MD (2024) Optimizing subretinal bleb formation for visual streak involvement in a Porcine model for retinal gene therapy. Invest Ophthalmol Vis Sci 65:41. https:\/\/doi.org\/10.1167\/iovs.65.12.41","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"6960_CR43","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1016\/j.ajo.2007.09.025","volume":"145","author":"QD Nguyen","year":"2008","unstructured":"Nguyen QD, Shah SM, Hafiz G, Do DV, Haller JA, Pili R, Zimmer-Galler IE, Janjua K, Symons RC, Campochiaro PA (2008) Intravenous bevacizumab causes regression of choroidal neovascularization secondary to diseases other than age-related macular degeneration. Am J Ophthalmol 145:257\u2013266. https:\/\/doi.org\/10.1016\/j.ajo.2007.09.025","journal-title":"Am J Ophthalmol"},{"key":"6960_CR44","doi-asserted-by":"publisher","first-page":"5420","DOI":"10.1109\/IEMBS.2010.5626493","volume":"2010","author":"BC Becker","year":"2010","unstructured":"Becker BC, Voros S, Lobes LA, Handa JT, Hager GD, Riviere CN (2010) Retinal vessel cannulation with an image-guided handheld robot. Annu Int Conf IEEE Eng Med Biol Soc 2010:5420\u20135423. https:\/\/doi.org\/10.1109\/IEMBS.2010.5626493","journal-title":"Annu Int Conf IEEE Eng Med Biol Soc"},{"key":"6960_CR45","doi-asserted-by":"publisher","first-page":"2951","DOI":"10.1109\/ICRA.2017.7989341","volume":"2017","author":"S Mukherjee","year":"2017","unstructured":"Mukherjee S, Yang S, MacLachlan RA, Lobes LA, Martel JN, Riviere CN (2017) Toward monocular Camera-Guided retinal vein cannulation with an actively stabilized handheld robot. IEEE Int Conf Robot Autom 2017:2951\u20132956. https:\/\/doi.org\/10.1109\/ICRA.2017.7989341","journal-title":"IEEE Int Conf Robot Autom"},{"key":"6960_CR46","doi-asserted-by":"publisher","first-page":"1676","DOI":"10.1007\/s10439-018-2053-3","volume":"46","author":"A Gijbels","year":"2018","unstructured":"Gijbels A, Smits J, Schoevaerdts L, Willekens K, Vander Poorten EB, Stalmans P, Reynaerts D (2018) In-human robot-assisted retinal vein cannulation, a world first. Ann Biomed Eng 46:1676\u20131685. https:\/\/doi.org\/10.1007\/s10439-018-2053-3","journal-title":"Ann Biomed Eng"},{"key":"6960_CR47","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1109\/TBME.2020.2996013","volume":"68","author":"SL Charreyron","year":"2021","unstructured":"Charreyron SL, Boehler Q, Danun AN, Mesot A, Becker M, Nelson BJ (2021) A magnetically navigated microcannula for subretinal injections. IEEE Trans Biomed Eng 68:119\u2013129. https:\/\/doi.org\/10.1109\/TBME.2020.2996013","journal-title":"IEEE Trans Biomed Eng"},{"key":"6960_CR48","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1016\/j.oret.2024.07.024","volume":"9","author":"A Shaheen","year":"2025","unstructured":"Shaheen A, Mehra D, Ghalibafan S, Patel S, Buali F, Panneerselvam S, Perez N, Hoyek S, Flynn HW, Patel N, Yannuzzi NA (2025) Efficacy and safety of anti-VEGF injections and surgery for age-related macular degeneration-related submacular hemorrhage: a systematic review and meta-analysis. Ophthalmol Retina 9:4\u201312. https:\/\/doi.org\/10.1016\/j.oret.2024.07.024","journal-title":"Ophthalmol Retina"},{"key":"6960_CR49","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1016\/j.jconrel.2022.10.036","volume":"352","author":"JH Jung","year":"2022","unstructured":"Jung JH, Kim SS, Chung H, Hejri A, Prausnitz MR (2022) Six-month sustained delivery of anti-VEGF from in-situ forming hydrogel in the suprachoroidal space. J Control Release 352:472\u2013484. https:\/\/doi.org\/10.1016\/j.jconrel.2022.10.036","journal-title":"J Control Release"},{"key":"6960_CR50","doi-asserted-by":"publisher","first-page":"900","DOI":"10.1038\/s41433-022-02194-0","volume":"37","author":"RN Hussain","year":"2023","unstructured":"Hussain RN, Damato B, Heimann H (2023) Choroidal biopsies; a review and optimised approach. Eye (Lond) 37:900\u2013906. https:\/\/doi.org\/10.1038\/s41433-022-02194-0","journal-title":"Eye (Lond)"},{"key":"6960_CR51","doi-asserted-by":"publisher","first-page":"879","DOI":"10.1080\/02713683.2024.2343335","volume":"49","author":"Z Stranak","year":"2024","unstructured":"Stranak Z, Ardan T, Nemesh Y, Toms M, Toualbi L, Harbottle R, Ellederova Z, Lytvynchuk L, Petrovski G, Motlik J, Moosajee M, Kozak I (2024) Feasibility of direct vitrectomy-sparing subretinal injection for gene delivery in large animals. Curr Eye Res 49:879\u2013887. https:\/\/doi.org\/10.1080\/02713683.2024.2343335","journal-title":"Curr Eye Res"}],"container-title":["Graefe's Archive for Clinical and Experimental Ophthalmology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00417-025-06960-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00417-025-06960-0\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00417-025-06960-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,4]],"date-time":"2025-12-04T03:50:59Z","timestamp":1764820259000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00417-025-06960-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,18]]},"references-count":51,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2025,11]]}},"alternative-id":["6960"],"URL":"https:\/\/doi.org\/10.1007\/s00417-025-06960-0","relation":{},"ISSN":["0721-832X","1435-702X"],"issn-type":[{"value":"0721-832X","type":"print"},{"value":"1435-702X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,9,18]]},"assertion":[{"value":"14 March 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 August 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 August 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 September 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Cadaveric porcine eyes were sourced post-mortem from a local abbatoir in compliance with local municipal animal welfare regulations. This work did not involve live animal studies therefore the Yokohama City University Animal Experimentation Committee was not required to review the study protocol, as per local institutional policy.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical Approval"}},{"value":"Author K.K. holds a patent for the 45G\/49G needle described in this work (Patent No. 5777074). Within the last 3 years author K.K. has had no other financial relationships or personal interests, including consultancies, equities or honoraria, related to the subject matter.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}