Abstract
Purpose
We evaluated the response of the retinal pigment epithelium (RPE) to high-density (HD) or low-density (LD)-selective retina therapy (SRT) with real-time feedback-controlled dosimetry (RFD) in rabbits.
Methods
Sixteen eyes of 8 Chinchilla Bastard rabbits underwent SRT with RFD (527-nm wavelength, 1.7-μs pulse duration), using automatically titrated pulse energy, by using optoacoustic dosimetry or real-time reflectometry. Fifty-six 25-μJ SRT, including LD-SRT (1-spot or 2-spot-spacing) and HD-SRT (4-spot, 7-spot, or 9-spot-no-spacing), were applied per eye. Color fundus photography and fundus fluorescein angiography (FFA) were used to confirm SRT spots 1-h post-SRT. Light microscopy and scanning electron microscopy (SEM) were performed at 2-h, 3-day, 7-day, and 1-month post-treatment.
Results
We tested 896 spots irradiated by SRT with RFD and confirmed that SRT lesions were adequate, based on invisibility on fundoscopy and visibility on FFA. On SEM, at 2-h post-SRT, flattened RPE cells were observed in the center of the SRT lesion. While normal RPE cells were clearly observed between LD-SRT lesions, healthy RPE cells were rare in HD-SRT lesions at 2-h post-treatment. At 7-day post-SRT, SEM revealed completely restored LD-SRT lesions with small or large RPE cells with microvilli, whereas HD-SRT lesions were covered with RPE cells without microvilli. At 1-month post-SRT, SEM revealed restored RPE cells with microvilli in HD-SRT lesions. On light microscopy, both HD- and LD-SRT lesions were completely restored with adjacent RPE cells and spared photoreceptors at 1-month post-treatment.
Conclusions
Although both HD- and LD-SRT lesions had recovered at 1-month post-SRT, LD-SRT lesions healed faster than HD-SRT lesions.
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Data availability
Not applicable.
References
The Diabetic Retinopathy Study Research Group (1981) Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of diabetic retinopathy study (DRS) findings, diabetic retinopathy study report number 8. Ophthalmology 88:583–600
Early Treatment Diabetic Retinopathy Study Research Group (1985) Photocoagulation for diabetic macular edema. Early treatment diabetic retinopathy study report number 1. Arch Ophthalmol 103:1796–1806
Lim JI (1999) Iatrogenic choroidal neovascularization. Surv Ophthalmol 44:95–111. https://doi.org/10.1016/s0039-6257(99)00077-6
Lewis H, Schachat AP, Haimann MH, Haller JA, Quinlan P, von Fricken MA, Fine SL, Murphy RP (1990) Choroidal neovascularization after laser photocoagulation for diabetic macular edema. Ophthalmology 97:503–510; discussion 510-501. https://doi.org/10.1016/s0161-6420(90)32574-5
Brinkmann R, Roider J, Birngruber R (2006) Selective retina therapy (SRT): a review on methods, techniques, preclinical and first clinical results. Bull Soc Belge Ophtalmol 302:51–69
Park YG, Seifert E, Roh YJ, Theisen-Kunde D, Kang S, Brinkmann R (2014) Tissue response of selective retina therapy by means of a feedback-controlled energy ramping mode. Clin Exp Ophthalmol 42:846–855. https://doi.org/10.1111/ceo.12342
Treumer F, Klettner A, Baltz J, Hussain AA, Miura Y, Brinkmann R, Roider J, Hillenkamp J (2012) Vectorial release of matrix metalloproteinases (MMPs) from porcine RPE-choroid explants following selective retina therapy (SRT): towards slowing the macular ageing process. Exp Eye Res 97:63–72. https://doi.org/10.1016/j.exer.2012.02.011
Richert E, Koinzer S, Tode J, Schlott K, Brinkmann R, Hillenkamp J, Klettner A, Roider J (2018) Release of different cell mediators during retinal pigment epithelium regeneration following selective retina therapy. Invest Ophthalmol Vis Sci 59:1323–1331. https://doi.org/10.1167/iovs.17-23163
Roider J, Brinkmann R, Wirbelauer C, Laqua H, Birngruber R (1999) Retinal sparing by selective retinal pigment epithelial photocoagulation. Arch Ophthalmol 117:1028–1034. https://doi.org/10.1001/archopht.117.8.1028
Roider J, Liew SH, Klatt C, Elsner H, Poerksen E, Hillenkamp J, Brinkmann R, Birngruber R (2010) Selective retina therapy (SRT) for clinically significant diabetic macular edema. Graefes Arch Clin Exp Ophthalmol 248:1263–1272. https://doi.org/10.1007/s00417-010-1356-3
Park YG, Kim JR, Kang S, Seifert E, Theisen-Kunde D, Brinkmann R, Roh YJ (2016) Safety and efficacy of selective retina therapy (SRT) for the treatment of diabetic macular edema in Korean patients. Graefes Arch Clin Exp Ophthalmol 254:1703–1713. https://doi.org/10.1007/s00417-015-3262-1
Park YG, Kang S, Kim M, Yoo N, Roh YJ (2017) Selective retina therapy with automatic real-time feedback-controlled dosimetry for chronic central serous chorioretinopathy in Korean patients. Graefes Arch Clin Exp Ophthalmol 255:1375–1383. https://doi.org/10.1007/s00417-017-3672-3
Schuele G, Elsner H, Framme C, Roider J, Birngruber R, Brinkmann R (2005) Optoacoustic real-time dosimetry for selective retina treatment. J Biomed Opt 10:064022. https://doi.org/10.1117/1.2136327
Minhee K, Park YG, Kang S, Roh YJ (2018) Comparison of the tissue response of selective retina therapy with or without real-time feedback-controlled dosimetry. Graefes Arch Clin Exp Ophthalmol 256:1639–1651. https://doi.org/10.1007/s00417-018-4067-9
Seifert E, Tode J, Pielen A, Theisen-Kunde D, Framme C, Roider J, Miura Y, Birngruber R, Brinkmann R (2018) Selective retina therapy: toward an optically controlled automatic dosing. J Biomed Opt 23:1–12. https://doi.org/10.1117/1.Jbo.23.11.115002
Valentino TL, Kaplan HJ, Del Priore LV, Fang SR, Berger A, Silverman MS (1995) Retinal pigment epithelial repopulation in monkeys after submacular surgery. Arch Ophthalmol 113:932–938. https://doi.org/10.1001/archopht.1995.01100070106033
Del Priore LV, Hornbeck R, Kaplan HJ, Jones Z, Valentino TL, Mosinger-Ogilvie J, Swinn M (1995) Debridement of the pig retinal pigment epithelium in vivo. Arch Ophthalmol 113:939–944. https://doi.org/10.1001/archopht.1995.01100070113034
Del Priore LV, Kaplan HJ, Hornbeck R, Jones Z, Swinn M (1996) Retinal pigment epithelial debridement as a model for the pathogenesis and treatment of macular degeneration. Am J Ophthalmol 122:629–643. https://doi.org/10.1016/s0002-9394(14)70481-7
Oganesian A, Bueno E, Yan Q, Spee C, Black J, Rao NA, Lopez PF (1997) Scanning and transmission electron microscopic findings during RPE wound healing in vivo. Int Ophthalmol 21:165–175. https://doi.org/10.1023/a:1026402031902
Sorensen NB, Lassota N, Kyhn MV, Prause JU, Qvortrup K, la Cour M, Kiilgaard J (2013) Functional recovery after experimental RPE debridement, mfERG studies in a porcine model. Graefes Arch Clin Exp Ophthalmol 251:2319–2325. https://doi.org/10.1007/s00417-013-2331-6
Kriechbaum K, Bolz M, Deak GG, Prager S, Scholda C, Schmidt-Erfurth U (2010) High-resolution imaging of the human retina in vivo after scatter photocoagulation treatment using a semiautomated laser system. Ophthalmology 117:545–551. https://doi.org/10.1016/j.ophtha.2009.07.031
Kiilgaard JF, Prause JU, Prause M, Scherfig E, Nissen MH, la Cour M (2007) Subretinal posterior pole injury induces selective proliferation of RPE cells in the periphery in in vivo studies in pigs. Invest Ophthalmol Vis Sci 48:355–360. https://doi.org/10.1167/iovs.05-1565
Framme C, Brinkmann R, Birngruber R, Roider J (2002) Autofluorescence imaging after selective RPE laser treatment in macular diseases and clinical outcome: a pilot study. Br J Ophthalmol 86:1099–1106. https://doi.org/10.1136/bjo.86.10.1099
Kang S, Park YG, Kim JR, Seifert E, Theisen-Kunde D, Brinkmann R, Roh YJ (2016) Selective retina therapy in patients with chronic central serous chorioretinopathy: a pilot study. Medicine 95:e2524. https://doi.org/10.1097/md.0000000000002524
Yasui A, Yamamoto M, Hirayama K, Shiraki K, Theisen-Kunde D, Brinkmann R, Miura Y, Kohno T (2017) Retinal sensitivity after selective retina therapy (SRT) on patients with central serous chorioretinopathy. Graefes Arch Clin Exp Ophthalmol 255:243–254. https://doi.org/10.1007/s00417-016-3441-8
Bonilha VL, Bhattacharya SK, West KA, Crabb JS, Sun J, Rayborn ME, Nawrot M, Saari JC, Crabb JW (2004) Support for a proposed retinoid-processing protein complex in apical retinal pigment epithelium. Exp Eye Res 79:419–422. https://doi.org/10.1016/j.exer.2004.04.001
Lamb TD, Pugh EN Jr (2004) Dark adaptation and the retinoid cycle of vision. Prog Retin Eye Res 23:307–380. https://doi.org/10.1016/j.preteyeres.2004.03.001
Roider J, Brinkmann R, Wirbelauer C, Laqua H, Birngruber R (2000) Subthreshold (retinal pigment epithelium) photocoagulation in macular diseases: a pilot study. Br J Ophthalmol 84:40–47. https://doi.org/10.1136/bjo.84.1.40
Guymer RH, Wu Z, Hodgson LAB, Caruso E, Brassington KH, Tindill N, Aung KZ, McGuinness MB, Fletcher EL, Chen FK, Chakravarthy U, Arnold JJ, Heriot WJ, Durkin SR, Lek JJ, Harper CA, Wickremasinghe SS, Sandhu SS, Baglin EK, Sharangan P, Braat S, Luu CD (2019) Subthreshold nanosecond laser intervention in age-related macular degeneration: the LEAD randomized controlled clinical trial. Ophthalmology 126:829–838. https://doi.org/10.1016/j.ophtha.2018.09.015
Chhablani J, Roh YJ, Jobling AI, Fletcher EL, Lek JJ, Bansal P, Guymer R, Luttrull JK (2018) Restorative retinal laser therapy: present state and future directions. Surv Ophthalmol 63:307–328. https://doi.org/10.1016/j.survophthal.2017.09.008
Tode J, Richert E, Koinzer S, Klettner A, von der Burchard C, Brinkmann R, Lucius R, Roider J (2019) Selective retina therapy reduces Bruch's membrane thickness and retinal pigment epithelium pathology in age-related macular degeneration mouse models. Transl Vis Sci Technol 8:11. https://doi.org/10.1167/tvst.8.6.11
Binder S, Krebs I, Hilgers RD, Abri A, Stolba U, Assadoulina A, Kellner L, Stanzel BV, Jahn C, Feichtinger H (2004) Outcome of transplantation of autologous retinal pigment epithelium in age-related macular degeneration: a prospective trial. Invest Ophthalmol Vis Sci 45:4151–4160. https://doi.org/10.1167/iovs.04-0118
Falkner-Radler CI, Krebs I, Glittenberg C, Povazay B, Drexler W, Graf A, Binder S (2011) Human retinal pigment epithelium (RPE) transplantation: outcome after autologous RPE-choroid sheet and RPE cell-suspension in a randomised clinical study. Br J Ophthalmol 95:370–375. https://doi.org/10.1136/bjo.2009.176305
Park YG, Kang S, Brinkmann R, Roh YJ (2015) A comparative study of retinal function in rabbits after panretinal selective retina therapy versus conventional panretinal photocoagulation. J Ophthalmol 2015:247259. https://doi.org/10.1155/2015/247259
Kim M, Park YG, Jeon SH, Choi SY, Roh Y-J (2020) The efficacy of selective retina therapy for diabetic macular edema based on pretreatment central foveal thickness. Lasers Med Sci https://doi.org/10.1007/s10103-020-02984-6
Daruich A, Matet A, Moulin A, Kowalczuk L, Nicolas M, Sellam A, Rothschild P-R, Omri S, Gélizé E, Jonet L, Delaunay K, De Kozak Y, Berdugo M, Zhao M, Crisanti P, Behar-Cohen F (2018) Mechanisms of macular edema: beyond the surface. Prog Retin Eye Res 63:20–68. https://doi.org/10.1016/j.preteyeres.2017.10.006
Prahs P, Walter A, Regler R, Theisen-Kunde D, Birngruber R, Brinkmann R, Framme C (2010) Selective retina therapy (SRT) in patients with geographic atrophy due to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 248:651–658. https://doi.org/10.1007/s00417-009-1208-1
Wang H, Van Patten Y, Sugino IK, Zarbin MA (2006) Migration and proliferation of retinal pigment epithelium on extracellular matrix ligands. J Rehabil Res Dev 43:713–722. https://doi.org/10.1682/jrrd.2005.06.0114
van Meurs JC, ter Averst E, Croxen R, Hofland L, van Hagen PM (2004) Comparison of the growth potential of retinal pigment epithelial cells obtained during vitrectomy in patients with age-related macular degeneration or complex retinal detachment. Graefes Arch Clin Exp Ophthalmol 242:442–443. https://doi.org/10.1007/s00417-003-0852-0
Rabenlehner D, Stanzel BV, Krebs I, Binder S, Goll A (2008) Reduction of iatrogenic RPE lesions in AMD patients: evidence for wound healing? Graefes Arch Clin Exp Ophthalmol 246:345–352. https://doi.org/10.1007/s00417-007-0658-6
Caramoy A, Fauser S, Kirchhof B (2012) Fundus autofluorescence and spectral-domain optical coherence tomography findings suggesting tissue remodelling in retinal pigment epithelium tear. Br J Ophthalmol 96:1211–1216. https://doi.org/10.1136/bjophthalmol-2012-301750
Funding
This study was supported by the grant from South Korean Government’s Ministry of Trade, Industry and Energy (M000004912–00192937). This animal study was supported by Research Institute of Medical Science of Yeouido St. Mary’s hospital.
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Conceived and designed the experiments: Young-Jung Roh; Performed the treatment: Young-Jung Roh; Analyzed the data: Seung Hee Jeon, Minhee Kim, Young-Jung Roh; Contributed reagents/materials/analysis tools: Seung Hee Jeon, Minhee Kim; Wrote the paper: Seung Hee Jeon, Minhee Kim, Young-Jung Roh; Approved final version of the manuscript: Seung Hee Jeon, Minhee Kim, Young-Jung Roh.
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YJ Roh has a patent related to real-time feedback dosimetry in South Korea, which is under the PCT application process. Lutronic and our research team jointly received funds from an international research and development project from the South Korean Government’s Ministry of Trade, Industry, and Energy (M000004912-00192937). Lutronic had a role in technical support.
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This study followed the ARVO Statement for the Use of Animals in Ophthalmic and Vision Research and was approved by the Institutional Animal Care and Use Committee of the Catholic University of Korea.
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Jeon, S., Kim, M. & Roh, YJ. Retinal pigment epithelial responses based on the irradiation density of selective retina therapy. Graefes Arch Clin Exp Ophthalmol 259, 101–111 (2021). https://doi.org/10.1007/s00417-020-04887-2
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DOI: https://doi.org/10.1007/s00417-020-04887-2