Autologous cultivated oral mucosal epithelial cell sheets to treat stem cell-deficient vision loss: A multi-centre clinical trial

Autologous cultivated oral mucosal epithelial cell sheets to treat stem cell-deficient vision loss: A multi-centre clinical trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Autologous cultivated oral mucosal epithelial cell sheets to treat stem cell-deficient vision loss: A multi-centre clinical trial Kohji Nishida, Yoshinori Oie, Takeshi Soma, Hiroshi Takayanagi, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7181420/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Limbal epithelial stem cells located at the corneal periphery are essential for maintaining the integrity of the corneal epithelium. Their depletion, known as a limbal stem cell deficiency (LSCD), can cause severe vision loss. Cultivated oral mucosal epithelial cell sheet transplantation (COMET) offers a promising treatment for LSCD. Here, six eyes of six patients underwent COMET in a prospective, multi-centre, government-controlled clinical trial. Only Good Gene, Cellular and Tissue-based Products Manufacturing Practice-compliant cell sheets were used, with follow-up for two years. The primary endpoint, corneal epithelial reconstruction, was successfully achieved in 100% of eyes at one year and 67% at two years. Visual acuity improved in 50% of eyes at both the one and two year examinations, with corneal opacification diminished in 33% and 50% of eyes, respectively. No clinically significant adverse events occurred throughout the whole follow-up period and the efficacy and safety of COMET was thus confirmed. The cell sheet, “Ocural”, is now approved as a Cellular and Tissue-Based Product, the world’s first regenerative medicine product for COMET. Trial registration numbers: UMIN000018662 ( https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000021510 ) registered on 13 August 2015. Health sciences/Health care/Therapeutics/Stem-cell therapies Health sciences/Diseases/Eye diseases/Corneal diseases Figures Figure 1 Figure 2 INTRODUCTION The cornea is the transparent “window” at the front of the eye that transmits light into the eye and helps focus it on the retina. Its anterior surface is overlaid with a stratified, non-keratinised epithelium, which is constantly renewed by stem cells that reside in the basal epithelium of the limbus, a transitional zone between the cornea and adjacent conjunctiva. 1 Limbal epithelial stem cells are highly proliferative, expressing p63 and exhibiting strong holoclone-forming capabilities. 2 , 3 If limbal stem cells are depleted by congenital disease or injury, however, an opacified and vascularised conjunctival pannus will envelop the cornea, severely disturbing vision. 4 – 7 This condition is called a limbal stem cell deficiency (LSCD). Although allogenic limbal transplantation has been used to treat LSCD, clinical outcomes are not always satisfactory because of postoperative complications that can include infectious keratitis or immunologic rejection. 8 , 9 To overcome these problems, cultivated autologous limbal stem cells, expanded into functional corneal epithelial cell sheets, have been successfully used for ocular surface reconstruction in patients with unilateral LSCD. 10 – 12 Indeed, clinical trials have confirmed the efficacy and safety of cultivated limbal epithelial cell sheet transplantation, 13 with the cell sheet (named Nepic) now approved as a cellular and tissue-based product in Japan. This type of autologous treatment, however, is only applicable for a unilateral LSCD because a healthy epithelial tissue from the unaffected eye is required from which a limbal graft biopsy can be obtained. To overcome the need for healthy limbal tissue as a cell source, we developed cultivated oral mucosal epithelial cell sheet transplantation (COMET), 14 – 16 which uses the patient’s oral mucosal epithelial cells as an alternative cell source. Accordingly, this method can be used to treat bilateral LSCD because the provision of healthy limbal epithelial cells is not required. After our initial report of COMET for LSCD, others reported encouraging results using similar techniques. 17 – 22 To date, however, all reports of COMET have limitations, either because of a retrospective single-centre study design or heterogeneity among transplanted cells due to the lack of evaluation under defined shipment criteria. Moreover, no clinical trial has been performed that adheres to Good Clinical Practice (GCP) stipulations within a defined clinical protocol and uses strict quality control for cell sheets fabricated in a Good Gene, Cellular, and Tissue-based Products Manufacturing Practice (GCTP) grade facility. Here, we report the outcome of a prospective, multicentre, government-controlled clinical trial using GCTP-derived cell sheets that confirms the efficacy and safety of COMET for LSCD. RESULTS Characteristics of the patients Nine eyes of nine patients were judged by the investigators to match the inclusion and exclusion criteria, however, three of these were deemed to be ineligible by the Eligibility Judgement Committee based on LSCD staging. Of the remaining six patients, four were treated at Osaka University Hospital, with one each enrolled at Tohoku University Hospital and the University of Tokyo Hospital. Six consecutive patients were enrolled between August 2015 and September 2017 after providing written informed consent. The mean age of the patients, three male and three female, was 59±27 years at the time of enrolment (median age 66 years; range 26–87 years). LSCD was caused by Stevens-Johnson syndrome (SJS) in two patients and mucous membrane pemphigoid (MMP) in two, with one suffering from aniridia. The other patient was idiopathic. Average preoperative visual acuity measured using Early Treatment of Diabetic Retinopathy Study (ETDRS) charts acuity was 2.18 ± 0.66 logMAR. All six operated eyes were categorised as LSCD Stage III (Table 1), meaning that the entire cornea was covered by conjunctiva. For each patient, the cultivated oral mucosal epithelial cell sheets, derived from biopsies of their own buccal mucosa, met all defined shipment criteria (Table S4). The planned number of cases has been enrolled, and the clinical trials have been completed. Endpoints for efficacy and safety The corneal epithelium was successfully reconstructed, as the primary endpoint of the trial, one year postoperatively in six of six eyes (100%; 95% confidence interval [CI] 54.1–100.0%), and was significantly higher than the 10%, clinically significant efficacy rate (P < 0.001, Fischer exact test). At two years, a successful epithelial reconstruction was achieved in four of six eyes (66.7%; 95% CI, 22.3–95.7%). Representative cases are shown in Figure 1. From this it can be seen that a patient without inflammation (C-3) had a clear cornea postoperatively, whereas a patient with early postoperative inflammation evidenced by severe hyperaemia (C-1) had a worse prognosis that included corneal opacification and neovascularisation. Preoperative and postoperative LSCD staging of all operated eyes is presented in Table 1. All six exhibited LSCD stage IA or IB at the one year postoperative timepoint, although two eyes had lapsed to stage IIB or III at 2 years. LSCD staging for the fellow eyes was mostly stable (Table S5). Postoperative changes and grading of subjective symptoms are shown in Table 2 and Tables S6-S11. Foreign body sensation and photophobia improved in three operated eyes (50%) one and two years postoperatively. There were no major changes in other subjective symptoms. As shown in Table 2 and S12, decimal visual acuity improved in the same three operated eyes (50%), one and two years postoperatively. ETDRS visual acuity improved in three operated eyes (50%) at 1 year and two eyes (33%) at 2 years (Table 2 and S13). Quality of Life (QOL) scores, shown in Table S14, improved in five (83%) patients at year one, and in three (50%) patients two years postoperatively. Corneal opacification improved in three (50%) eyes, one and two years postoperatively (Table 2 and S15). Corneal neovascularisation improved in three (50%) operated eyes at one and two years (Table 2 and S16). No significant changes in symblepharon (Table 2 and S17), a partial or complete adhesion of the palpebral conjunctiva of the eyelid to the bulbar conjunctiva of the eyeball, were noted throughout the follow-up. With regards to safety endpoints, superficial punctate keratitis was observed in all operated and fellow eyes (100%) preoperatively and postoperatively. Corneal epithelial defects were not seen in any of the operated or fellow eyes preoperatively, but after surgery it was observed in five operated eyes (83%) and three fellow eyes (50%). Keratinisation was observed in one fellow eye (17%). Conjunctival hyperaemia was a feature of all eyes preoperatively and was observed in all operated eyes and five of six fellow eyes (83%), postoperatively. Infectious keratitis or endophthalmitis were not observed. We observed three serious adverse events, as defined by the clinical protocols (Supplemental Files), which required hospitalisation for treatment. These comprised one case of cellulitis (16.7%), one of dacryocystitis (16.7%) and another of cataract in the unoperated eye (16.7%). All adverse events (Tables S18 to S21) were treated successfully and did not result in any residual effects. A causal relationship with the COMET surgery or cell sheets was ruled out for all adverse events. DISCUSSION Here, we describe the world’s first government-controlled clinical trial that follows a prospective multicentre clinical study design (Supplementary Files) using cultivated oral mucosal epithelial cell sheets. The sheets were generated in a GCTP-grade facility, with strict quality control oversight, and were used in adherence to GCP guidelines and a defined clinical protocol. Evaluation of the primary endpoints was objectively conducted by third-party cornea specialists using anonymously and randomly provided clinical photographs, without any accompanying information. As a primary efficacy endpoint, the corneal epithelium was successfully reconstructed in 100% and 66.7% of eyes at postoperative years one and two, respectively. Visual acuity improved significantly in 50% of treated eyes at one and two years, as did corneal opacification and neovascularisation. Importantly, we did not experience any clinically significant adverse events. Data were reviewed by the Ministry of Health, Labor and Welfare in Japan, after which the autologous cultivated oral mucosal epithelial cell sheet was approved as a Cellular and Tissue-based product, called “Ocural”, in Japan. This represents the world’s first approval of a cultivated oral mucosal epithelial cell sheet for use in eye surgery. Our primary endpoint measure, a corneal epithelial reconstruction success rate of 100% at postoperative year one and 67% at postoperative year two is higher than the clinically significant success rate of 10% achieved by conventional allogenic limbal transplantation. A related clinical study conducted by us (Supplementary Appendix) uncovered a 100% success rate for COMET outcomes in 26 LSCD patients, although a different clinical grading system was used in that research because the global consensus for LSCD classification 4 had not yet been established. The success rate reported here, we note, is also similar to the ocular surface reconstruction success rate reported in previous review articles describing COMET, as shown in Table 3, 23-26 and to the 60-85% success following cultivated limbal epithelial cell sheet transplantation. 13,27,28 A significant feature of the current study is that the success rate was evaluated by third-party endpoint evaluators who were provided with slit-lamp photographs anonymously and in random order. Two eyes of two patients in this trial were complicated by early postoperative inflammation (Figure 1). Previous investigations have also shown that failed cases of cultivated limbal epithelial cell sheet transplantation could be accompanied by severe early postoperative inflammation and subsequent conjunctival invasion onto the central cornea. 13 Therefore, postoperative inflammation after surgeries of these types needs to be carefully monitored and well managed if a good long-term prognosis is to be achieved. However, achieving complete control of inflammation remains a challenge, as causative diseases such as SJS or MMP often provoke severe inflammation that is resistant to current therapeutic options. The improvement of visual acuity in 50% of cases reported here is judged to be a highly positive outcome when we remember that we only performed cultivated epithelial cell sheet transplantation, and visual acuity can be negatively influenced by a host of unrelated ocular disorders such as corneal stromal opacification, cataract, glaucoma and/or retinal pathology. Our study of the clinical outcomes of COMET conducted prior to the creation of the global consensus of LSCD by Deng and associates on behalf of The International LSCD Working Group, 4 likewise showed improved visual acuity in 50% of cases one year postoperatively, and 63.6% of cases at postoperative year two (including those receiving keratoplasty for corneal stromal opacification). Corneal opacification and neovascularisation improved in 50% cases in our clinical trial, reported here, with the rate similar to that seen in our related clinical study of 22 patients with LSCD (Supplementary Appendix). With regards to safety endpoints, we experienced three serious adverse events defined by the clinical protocol in this clinical trial at postoperative year two (five events occurred our pre-global consensus clinical study (Supplementary Appendix)). We judge that none of the serious adverse events in the clinical trial were caused by the tissue collection or investigational product. Some of the serious adverse events in the clinical study were felt to be related to the treatment but all were successfully treated without permanent damage (Supplementary Appendix). Ocular hypertension occurred in 16.7% of cases (n = 1 of 6) in the clinical trial and 40.9% of cases (n = 9 of 22) in the clinical study, but all eyes were adequately treated without ongoing symptoms. Immunological rejection and infectious keratitis were not seen. A limitation of our studies, including both clinical trials with 6 patients and clinical study with 22 cases, is the relatively small number of total cases. This limits the generalizability of our findings and precludes definitive conclusions regarding the direct comparisons with other treatments for LSCD. We recently published the results of a first-in-human interventional study using human induced pluripotent stem-cell-derived corneal epithelium involving four patients with LSCD. 29 Although the results were positive, only a small number of patients were studied, and confirmation from a larger multicentre clinical trial is required to adopt this approach. As a current alternative, autologous COMET, described here, is a safe and effective treatment for LSCD, as established in this government-controlled clinical trial of a newly approved Cellular and Tissue-based product for ocular regenerative medicine. Methods Study design and trial oversight We conducted a prospective, multicentre, open-label, uncontrolled, single-arm clinical trial to establish the efficacy and safety of graft surgery employing autologous cultivated oral mucosal epithelial cell sheets (the investigational product). Detailed clinical protocols are provided in the supplemental files. The initial physician-oriented clinical trial had a postoperative follow-up period of one year, extended to two years for in the same cohort of patients via an additional one-year follow-up. In the initial trial, patient monitoring comprised an observation period before surgery and a follow-up period postoperatively (Tables S1 to S3). The trial protocol was approved by the Institutional Review Boards of each participating institute (Osaka University Hospital, Tohoku University Hospital, University of Tokyo Hospital) and by the Ministry of Health, Labor and Welfare of Japan. The trial was conducted according to tenets of the Declaration of Helsinki and was registered as UMIN000018662. Patients and endpoints Inclusion criteria for the clinical trial were as follows: 1) Patients diagnosed with stage III LSCD 4 ; 2) a lack of extensive oral mucosal scarring and the presence of healthy oral mucosal tissue for harvest; 3) patients ≥20-years-old at the time of informed consent. Detailed exclusion criteria are described in the clinical protocols (Supplemental File). The trial’s primary endpoint was the success rate of corneal epithelial reconstruction (%) one and two years after transplantation of the oral mucosal epithelial cell sheet as the investigational device. LSCD staging was evaluated according to the criteria agreed by global consensus, 4 not only in the operated eye but the fellow eye, too. After surgery, if the operated eye was evaluated as being LSCD stage IA to C, the surgery was considered to be a success. LSCD diagnosis and staging was initially conducted by on-site corneal specialists aided by slit-lamp examination, including fluorescein staining. It was finally determined by the trial’s Eligibility Judgment Committee and Effect Assessment Committee using slit-lamp photographs, including fluorescein staining. Both committees were composed of 2-3 third-party cornea specialists, who were provided with slit-lamp photographs anonymously and in random order. Two-sided 95% confidence intervals (CI) for the primary endpoint were calculated using the Clopper–Pearson method. Success rates one year postoperatively were determined using an exact binomial test at a two-sided alpha level of 5% to examine the null hypothesis that the success rate would be 10%. (Supplemental File). Secondary endpoints for efficacy were as follows: 1) LSCD stage after transplantation of the investigational product; 2) Subjective symptoms; 3) Corrected visual acuity using a decimal visual acuity chart and an ETDRS chart; 4) Quality of life (QOL) as evaluated by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ25); 5) Severity of corneal opacity; 30 6) Severity of corneal neovascularisation; 30 7) Severity of symblepharon. 30 We also evaluated whether or not additional treatment to improve visual acuity was indicated at one-year, and whether or not this contributed to the restoration of the corneal surface at the two-year juncture in subjects who received additional treatment. We also evaluated the untreated contralateral eye for LSCD stage, subjective symptoms, corrected visual acuity, severity of corneal opacity, corneal neovascularisation and symblepharon. Visual acuity is presented as logMAR (logarithm of the minimum angle of resolution) values, with improvements of more than two lines regarded as significant. Improvement of one or more grades for corneal opacification, neovascularisation and symblepharon were considered significant. The occurrence of superficial punctate keratopathy, the presence of corneal epithelial defects, corneal keratinisation, conjunctival hyperaemia, infectious keratitis and endophthalmitis up to one-year were assessed as safety criteria. Adverse events and malfunctions of the investigational device (i.e. the COMET cell sheet) were also recorded and converted to standard terms using the Medical Dictionary for Regulatory Activities (MedDRA) /J Ver21.0. The analysis methods are described in detail in the study analysis plan. (Supplemental files) No important changes were made after the trial commenced. Cell sheet fabrication and quality control For each patient an oral mucosal tissue biopsy, approximately 50 mm 2 in size, was obtained from the buccal mucosa, after which cells were dissociated and cultivated on temperature responsive culture surfaces as previously reported. (Figure 2) 13,14,31 Virus validated, lethally irradiated 3T3-J2 cells from an established working cell bank were used as feeder cells. All cell sheets were fabricated in a GMP-grade facility managed by Japan Tissue Engineering Co. Ltd (Gamagori, Japan) under established standard operating procedures (SOPs), guided and recorded under a process management system. Cell sheets were evaluated using defined shipment criteria before transplantation, and only those that met the criteria were used for transplantation. Cell sheets were transported from the GCTP-grade facility to transplantation facilities using a specially designed container. 32 Transplantation and post-operative care A single expanded oral mucosal epithelial cell sheet was transplanted onto each of the patients diseased eyes as described in detail elsewhere. 13,14 Briefly, superficial conjunctival scar tissue that enveloped the corneal surfaces was dissected away to expose bare corneal stroma up to 3 mm outside the limbus. The cell sheet, which had been lifted from its temperature-responsive culture dish, was then grafted directly onto the corneal stroma and a therapeutic soft contact lens placed on the eye for protection. Postoperative local medication included topical antibiotics (0.5% cefmenoxime) and corticosteroids (0.1% betamethasone) as eye drops four times a day, along with betamethasone and fradiomycin ointment once a day. Betamethasone eye drops were switched to 0.1% fluorometholone eye drops 3–6 months after surgery depending on the level of inflammation seen in individual eyes. Systemic corticosteroid was administered as 125 mg methylprednisolone on the day of surgery, followed by 2 mg of betamethasone for two days and 1 mg of betamethasone for 1 month with tapering. We administered systemic corticosteroid only in cases where the ocular surface inflammation could not be suppressed with corticosteroid eye drops. Some patients experienced severe dry eye, and self-administered artificial tears. Declarations COMPETING INTEREST This work was supported by AMED (grant number JP17ek0109005) and Japan Tissue Engineering Co., Ltd, Gamagori, Japan. Y.O. reports a consulting fee and travel support. K.N. reports a consulting fee, payment for lectures and travel support. T.O. and M.I. are employee of Japan Tissue Engineering Co., Ltd. No other potential conflict of interest relevant to this article is reported. DATA AVAILABILITY All deidentified participant data, including individual participant data and the trial protocol are available in the appendix and will be available with no end date. References Cotsarelis, G., Cheng, S. Z., Dong, G., Sun, T. T. & Lavker, R. M. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. Cell 57 , 201–209 (1989). https://doi.org/10.1016/0092-8674(89)90958-6 Pellegrini, G. et al. Location and clonal analysis of stem cells and their differentiated progeny in the human ocular surface. J. Cell Biol. 145 , 769–782.1 https://doi.org/10.1083/jcb.145.4.769 Pellegrini, G. et al. p63 identifies keratinocyte stem cells. Proc. Natl Acad. Sci. U. S. A. 98 , 3156–3161 (2001). https://doi.org/10.1073/pnas.061032098 Deng, S. X. et al. Global consensus on definition, classification, diagnosis, and staging of limbal stem cell deficiency. Cornea 38 , 364–375 (2019). https://doi.org/10.1097/ico.0000000000001820 Oie, Y. & Nishida, K. Corneal regenerative medicine. Regen. Ther. 5 , 40-45 (2016). https://doi.org/10.1016/j.reth.2016.06.002 Oie, Y. & Nishida, K. Evaluation of corneal neovascularization using optical coherence tomography angiography in patients with limbal stem cell deficiency. Cornea 36 , S72-S75 (2017). https://doi.org/10.1097/ico.0000000000001382 Kiritoshi, S. et al. Anterior segment optical coherence tomography angiography in patients following cultivated oral mucosal epithelial transplantation. Am. J. Ophthalmol. 208 , 242-250 (2019). https://doi.org/10.1016/j.ajo.2019.08.006 Tsubota, K. et al. Treatment of severe ocular-surface disorders with corneal epithelial stem-cell transplantation. N. Engl. J. Med. 340 , 1697–1703 (1999). https://doi.org/10.1056/nejm199906033402201 Ilari, L. & Daya, S. M. Long-term outcomes of keratolimbal allograft for the treatment of severe ocular surface disorders. Ophthalmology 109 , 1278–1284 (2002). https://doi.org/10.1016/s0161-6420(02)01081-3 Pellegrini, G. et al. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet 349 , 990–993 (1997). https://doi.org/10.1016/s0140-6736(96)11188-0 Rama, P. et al. Limbal stem-cell therapy and long-term corneal regeneration. N. Engl. J. Med. 363 , 147–155 (2010). https://doi.org/10.1056/nejmoa0905955 Jurkunas, U.V. et al. Cultivated autologous limbal epithelial cell (CALEC) transplantation for limbal stem cell deficiency: a phase I/II clinical trial of the first xenobiotic-free, serum-free, antibiotic-free manufacturing protocol developed in the US. Nat. Commun. 16 , 1607 (2025). https://doi.org/10.1038/s41467-025-56461-1 Oie, Y. et al. Clinical trial of autologous cultivated limbal epithelial cell sheet transplantation for patients with limbal stem cell deficiency. Ophthalmology 130 , 608–614 (2023). https://doi.org/10.1016/j.ophtha.2023.01.016 Nishida, K. et al. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. N. Engl. J. Med. 351 , 1187–1196 (2004). https://doi.org/10.1056/nejmoa040455 Soma, T. et al. Maintenance and distribution of epithelial stem/progenitor cells after corneal reconstruction using oral mucosal epithelial cell sheets. PLOS One 9 , e110987 (2014). https://doi.org/10.1371/journal.pone.0110987 Oie, Y. & Nishida, K. Translational research on ocular surface reconstruction using oral mucosal epithelial cell sheets. Cornea 33 (Suppl 11), S47-S52 (2014). https://doi.org/10.1097/ico.0000000000000232 Nakamura, T. et al. Transplantation of cultivated autologous oral mucosal epithelial cells in patients with severe ocular surface disorders. Br. J. Ophthalmol. 88 , 1280–1284 (2004). https://doi.org/10.1136/bjo.2003.038497 Inatomi, T., Nakamura, T., Koizumi, N., Sotozono, C. & Kinoshita, S. Current concepts and challenges in ocular surface reconstruction using cultivated mucosal epithelial transplantation. Cornea 24 (8)(Suppl), S32–S38 (2005). https://doi.org/10.1097/01.ico.0000178739.37083.2c Ma, D. H. et al. Transplantation of cultivated oral mucosal epithelial cells for severe corneal burn. Eye (Lond.) 23 , 1442–1450 (2009). https://doi.org/10.1038/eye.2009.60 Nakamura, T., Takeda, K., Inatomi, T., Sotozono, C. & Kinoshita, S. Long-term results of autologous cultivated oral mucosal epithelial transplantation in the scar phase of severe ocular surface disorders. Br. J. Ophthalmol. 95 , 942–946 (2011). https://doi.org/10.1136/bjo.2010.188714 Satake, Y., Higa, K., Tsubota, K. & Shimazaki, J. Long-term outcome of cultivated oral mucosal epithelial sheet transplantation in treatment of total limbal stem cell deficiency. Ophthalmology 118 , 1524–1530 (2011). https://doi.org/10.1016/j.ophtha.2011.01.039 Burillon, C. et al. Cultured autologous oral mucosal epithelial cell sheet (CAOMECS) transplantation for the treatment of corneal limbal epithelial stem cell deficiency. Invest. Ophthalmol. Vis. Sci. 53 , 1325–1331 (2012). https://doi.org/10.1167/iovs.11-7744 Utheim, T. P. Concise review: transplantation of cultured oral mucosal epithelial cells for treating limbal stem cell deficiency-current status and future perspectives. Stem Cells 33 , 1685–1695 (2015). https://doi.org/10.1002/stem.1999 Oie, Y., Komoto, S. & Kawasaki, R. Systematic review of clinical research on regenerative medicine for the cornea. Jpn. J. Ophthalmol. 65 , 169–183 (2021). https://doi.org/10.1007/s10384-021-00821-z Cabral, J. V., Jackson, C. J., Utheim, T. P. & Jirsova, K. Ex vivo cultivated oral mucosal epithelial cell transplantation for limbal stem cell deficiency: a review. Stem Cell Res. Ther. 11 , 301 (2020). https://doi.org/10.1186/s13287-020-01783-8 Figueiredo, F. C. et al. A systematic review of cellular therapies for the treatment of limbal stem cell deficiency affecting one or both eyes. Ocul. Surf. 20 , 48–61 (2021). https://doi.org/10.1016/j.jtos.2020.12.008 Le, Q., Chauhan, T., Yung, M., Tseng, C. H. & Deng, S. X. Outcomes of limbal stem cell transplant: A meta-analysis. JAMA Ophthalmol. 138 , 660–670 (2020). https://doi.org/10.1001/jamaophthalmol.2020.1120 Zhao, Y. & Ma, L. Systematic review and meta-analysis on transplantation of ex vivo cultivated limbal epithelial stem cell on amniotic membrane in limbal stem cell deficiency. Cornea 34 , 592–600 (2015). https://doi.org/10.1097/ico.0000000000000398 Soma, T. et al. Induced pluripotent stem-cell-derived corneal epithelium for transplant surgery: a single-arm, open-label, first-in-human interventional study in Japan. Lancet 404 , 1929–1939 (2024). https://doi.org/10.1016/s0140-6736(24)01764-1 Sotozono, C. et al. New grading system for the evaluation of chronic ocular manifestations in patients with Stevens-Johnson syndrome. Ophthalmology 114 , 1294–1302 (2007). https://doi.org/10.1016/j.ophtha.2006.10.029 Nishida, K. et al. Functional bioengineered corneal epithelial sheet grafts from corneal stem cells expanded ex vivo on a temperature-responsive cell culture surface. Transplantation 77 , 379–385 (2004). https://doi.org/10.1097/01.tp.0000110320.45678.30 Oie, Y. et al. Development of a cell sheet transportation technique for regenerative medicine. Tissue Eng. Part C Methods 20 , 373–382 (2014). https://doi.org/10.1089/ten.tec.2013.0266 Tables Table 1. LSCD staging of operated eyes following cultivated oral mucosal epithelial cell sheets transplantation Patient anonymisation number Age Sex Causative disease Preoperative stage 2 weeks 4 weeks 12 weeks 24 weeks 52 weeks 78 weeks 104 weeks A-3 57 F Congenital aniridia III IB IA IA IA IB IIB III B-1 75 F SJS III IA IA IA IA IA IA IA C-1 28 M SJS III IA IA IA IA IA IIB IIB C-2 80 F MMP III IA IA IA IA IA IA IB C-3 26 M Idiopathic III IA IA IA IA IA IA IA C-5 87 M MMP III IA IA IA IA IA IA IA LSCD: limbal stem cell deficiency, SJS: Stevens-Johnson syndromed, MMP: mucous membrane pemphigoid Table 2. Postoperative changes of subjective symptoms, visual acuity, corneal opacification, corneal neovascularisation, and symblepharon Eye Change Ocular pain Foreign body sensation Lacrimation Photophobia Dryness Discomfort 52 weeks 104 weeks 52 weeks 104 weeks 52 weeks 104 weeks 52 weeks 104 weeks 52 weeks 104 weeks 52 weeks 104 weeks Operated eye Improved 2 (33%) 0 (0%) 3 (50%) 3 (50%) 1 (17%) 1 (17%) 3 (50%) 3 (50%) 1 (17%) 1 (17%) 3 (50%) 2 (33%) Unchanged 4 (67%) 4 (67%) 2 (33%) 2 (33%) 5 (83%) 5 (83%) 2 (33%) 2 (33%) 3 (50%) 4 (67%) 2 (33%) 2 (33%) Deteriorated 0 (0%) 2 (33%) 1 (17%) 1 (17%) 0 (0%) 0 (0%) 1 (17%) 1 (17%) 2 (33%) 1 (17%) 1 (17%) 2 (33%) Fellow eye Improved 0 (0%) 0 (0%) 1 (17%) 1 (17%) 1 (17%) 1 (17%) 1 (17%) 2 (33%) 1 (17%) 0 (0%) 1 (17%) 1 (17%) Unchanged 4 (67%) 6 (100%) 4 (67%) 4 (67%) 5 (83%) 5 (83%) 2 (33%) 2 (33%) 4 (67%) 5 (83%) 3 (50%) 2 (33%) Deteriorated 2 (33%) 0 (0%) 1 (17%) 1 (17%) 0 (0%) 0 (0%) 3 (50%) 2 (33%) 1 (17%) 1 (17%) 2 (33%) 3 (50%) Eye Change Decimal visual acuity ETDRS visual acuity Corneal opacification Corneal neovascularisation Symblepharon 52 weeks 104 weeks 52 weeks 104 weeks 52 weeks 104 weeks 52 weeks 104 weeks 52 weeks 104 weeks Operated eye Improved 3 (50%) 3 (50%) 3 (50%) 2 (33%) 3 (50%) 3 (50%) 3 (50%) 3 (50%) 0 (0%) 0 (0%) Unchanged 2 (33%) 2 (33%) 2 (33%) 3 (50%) 3 (50%) 3 (50%) 3 (50%) 3 (50%) 6 (100%) 6 (100%) Deteriorated 1 (17%) 1 (17%) 1 (17%) 1 (17%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) Fellow eye Improved 0 (0%) 3 (50%) 1 (17%) 3 (50%) 2 (33%) 3 (50%) 1 (17%) 0 (0%) 0 (0%) 0 (0%) Unchanged 2 (33%) 2 (33%) 2 (33%) 2 (33%) 4 (67%) 3 (50%) 5 (83%) 5 (83%) 5 (83%) 6 (100%) Deteriorated 4 (67%) 1 (17%) 3 (50%) 1 (17%) 0 (0%) 0 (0%) 0 (0%) 1 (17%) 1 (17%) 0 (0%) ETDRS: Early Treatment of Diabetic Retinopathy Study Table 3. Comparison of clinical outcomes between the current clinical trial and meta-analysis or systematic review Current clinical trial (N=6) Utheim TP. Stem Cells 2015 23 Oie Y et al. Jpn J Ophthalmol 2021 24 Cabral JV et al. Stem Cell Res Ther 2020 25 Figueiredo FC et al. Ocul Surf 2021 26 Corneal epithelium reconstruction 100% (1 year) 66.7% (2 years) 72% 66.7% 70.8% 71.4% Visual recovery 50% (1 year) 50% (2 years) 68% 66.7% 63.5% - Ocular hypertension 16.7% 9% (including glaucoma) 8.1% (including glaucoma) - - Immunological rejection 0% - 0% - - Infectious keratitis 0% 1.6% 5.3% - - Additional Declarations Yes there is potential Competing Interest. This work was supported by AMED (grant number JP17ek0109005) and Japan Tissue Engineering Co., Ltd, Gamagori, Japan. Y.O. reports a consulting fee and travel support. K.N. reports a consulting fee, payment for lectures and travel support. T.O. and M.I. are employee of Japan Tissue Engineering Co., Ltd. No other potential conflict of interest relevant to this article is reported. Supplementary Files supplementalfile3tablecomparingprotocolforclinicaltrial.doc supplemental file3 supplementalfile2originalclinicalprotocolforclinicaltrial.docx supplemental file2 supplementalfile5finalSAPforclinicaltrial.docx supplemental file5 supplementalfile10tablecomparingSAPforfollowupclinicaltrial.doc supplemental file10 supplementalfile8finalSAPforfollowupclinicaltrial.docx supplemental file8 supplementalfile6originalSAPforclinicaltrial.docx supplemental file6 supplementaryappendixfile20241223XXXXXXXXXXXXXXXXXXXXXXXXYO2.docx supplementary appendix file supplementalfile12clinicalprotocolforclinicalstudyclean.doc supplemental file12 supplementalfile11clinicalstudyver.3.docx supplemental file11 supplementalfile7tablecomparingSAPforclinicaltrial.doc supplemental file7 supplementalfile1finalclinicalprotocolforclinicaltrial.docx supplemental file1 supplementalfile9originalSAPforfollowupclinicaltrial.docx supplemental file9 supplementalfile4clinicalprotocolforfollowuptrial.docx supplemental file4 Cite Share Download PDF Status: Under Review Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7181420","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":513082062,"identity":"2b3576cc-1fc1-4262-942a-95d78f2b5bd5","order_by":0,"name":"Kohji Nishida","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzklEQVRIiWNgGAWjYDACZgY2hgQ2BgN+ECehgBQtkg0gLQbE2cMGQgYGB0BsYrSYs7M/e/CgzM7Y+PzqxA8PDBjk+cUO4Ndi2cxjbpBwLtnM7MbbzRJAhxnOnJ2AX4vBYR42icQ2ZhuzG2c3gLQkGNwmqIX9GVBLvY3xjLObfxCphcEMqOWwmQF/7zZibeExk0g4d9xY4gbvNosEAwki/HL++DPJH2XVhv39Zzff/FFhI88vTUALAkiAVUoQqxwE+A+QonoUjIJRMApGEgAA5gJA/uz5hj8AAAAASUVORK5CYII=","orcid":"","institution":"the University of Osaka","correspondingAuthor":true,"prefix":"","firstName":"Kohji","middleName":"","lastName":"Nishida","suffix":""},{"id":513082063,"identity":"2ad47fae-857b-430b-9238-f3f2acb2e8fa","order_by":1,"name":"Yoshinori Oie","email":"","orcid":"","institution":"the University of Osaka","correspondingAuthor":false,"prefix":"","firstName":"Yoshinori","middleName":"","lastName":"Oie","suffix":""},{"id":513082064,"identity":"79b5d8e8-3b22-4202-b2a8-b567c5d3ac76","order_by":2,"name":"Takeshi Soma","email":"","orcid":"","institution":"Osaka University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Takeshi","middleName":"","lastName":"Soma","suffix":""},{"id":513082065,"identity":"f1394492-6237-454a-9c38-dd633b325aec","order_by":3,"name":"Hiroshi Takayanagi","email":"","orcid":"","institution":"the University of Osaka","correspondingAuthor":false,"prefix":"","firstName":"Hiroshi","middleName":"","lastName":"Takayanagi","suffix":""},{"id":513082066,"identity":"f16f935a-51df-4046-8a7c-aaa13379b4c3","order_by":4,"name":"Shunji Yokokura","email":"","orcid":"","institution":"Tohoku University","correspondingAuthor":false,"prefix":"","firstName":"Shunji","middleName":"","lastName":"Yokokura","suffix":""},{"id":513082067,"identity":"06198a81-2e58-434b-8487-5142046f927a","order_by":5,"name":"Toru Nakazawa","email":"","orcid":"https://orcid.org/0000-0002-5591-4155","institution":"Tohoku University Graduate School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Toru","middleName":"","lastName":"Nakazawa","suffix":""},{"id":513082068,"identity":"50c23d09-ead8-4d09-bd01-422b3e5f1da7","order_by":6,"name":"Tomohiko Usui","email":"","orcid":"","institution":"the University of Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Tomohiko","middleName":"","lastName":"Usui","suffix":""},{"id":513082069,"identity":"e5dc0dba-b26c-4eda-90d1-7853ce438dd4","order_by":7,"name":"Shiro Amano","email":"","orcid":"","institution":"the University of Tokyo","correspondingAuthor":false,"prefix":"","firstName":"Shiro","middleName":"","lastName":"Amano","suffix":""},{"id":513082070,"identity":"5fc2011f-b306-4990-bdcd-ba0234aaea47","order_by":8,"name":"Yuko Hara","email":"","orcid":"","institution":"Ehime University","correspondingAuthor":false,"prefix":"","firstName":"Yuko","middleName":"","lastName":"Hara","suffix":""},{"id":513082071,"identity":"7547d13e-2aef-4632-8336-93c0de0494a3","order_by":9,"name":"Atsushi Shiraishi","email":"","orcid":"","institution":"Ehime University","correspondingAuthor":false,"prefix":"","firstName":"Atsushi","middleName":"","lastName":"Shiraishi","suffix":""},{"id":513082072,"identity":"c3136754-2ef3-4f99-80a8-96f0533d45fa","order_by":10,"name":"Shoko Matsubara","email":"","orcid":"","institution":"the University of Osaka","correspondingAuthor":false,"prefix":"","firstName":"Shoko","middleName":"","lastName":"Matsubara","suffix":""},{"id":513082073,"identity":"45182684-eef0-44de-9815-83f3dcdb8e13","order_by":11,"name":"Kiyoshi Okada","email":"","orcid":"","institution":"the University of Osaka","correspondingAuthor":false,"prefix":"","firstName":"Kiyoshi","middleName":"","lastName":"Okada","suffix":""},{"id":513082074,"identity":"3d162acc-7c58-4f6c-bcb3-e5fec10c6fbb","order_by":12,"name":"Takahiro Ogasawara","email":"","orcid":"","institution":"Japan Tissue Engineering Co., Ltd","correspondingAuthor":false,"prefix":"","firstName":"Takahiro","middleName":"","lastName":"Ogasawara","suffix":""},{"id":513082075,"identity":"2d6a238e-85b7-4638-8433-71eddb238df1","order_by":13,"name":"Masukazu Inoie","email":"","orcid":"","institution":"Japan Tissue Engineering Co., Ltd.","correspondingAuthor":false,"prefix":"","firstName":"Masukazu","middleName":"","lastName":"Inoie","suffix":""},{"id":513082076,"identity":"f4d9e19b-65e6-4e30-8408-45e481b2016f","order_by":14,"name":"Andrew Quantack","email":"","orcid":"","institution":"Cardiff University","correspondingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"","lastName":"Quantack","suffix":""}],"badges":[],"createdAt":"2025-07-22 01:20:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7181420/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7181420/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105197005,"identity":"77594220-6dbe-44a5-a078-e790e345ff03","added_by":"auto","created_at":"2026-03-23 10:27:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1356831,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEyes before and after transplantation of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eex vivo\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e expanded autologous oral mucosalepithelial cell sheets\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe corneal surface was successfully reconstructed using ex vivo expanded autologous oral mucosal epithelial cell sheets, resulting in improved and maintained corneal transparency consistently up to two years postoperatively as indicated in case C-3. However, in case C-1 with SJS, severe inflammation was observed at 12 weeks, with conjunctivalisation noted two years postoperatively.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7181420/v1/3035556029f7318ffe4f3cf2.png"},{"id":105197092,"identity":"82c686d9-4983-4db1-90a8-8b6dad4490d1","added_by":"auto","created_at":"2026-03-23 10:27:58","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":883132,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTransplantation of \u003c/strong\u003e\u003cem\u003e\u003cstrong\u003eex vivo\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e expanded autologous oral mucosal epithelial cell sheets\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA small biopsy of healthy oral mucosal tissue is collected from the patient's buccal mucosa after which oral mucosal epithelial stem cells are isolated and cultured on a temperature-responsive cell culture dish. Once the \u003cem\u003eex vivo\u003c/em\u003e expanded autologous oral mucosal epithelial cell sheet has formed, it is detached from the culture dish by lowering the temperature to room temperature, enabling it to be carefully lifted and transplanted onto the surface of the diseased eye.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7181420/v1/f654fda72c9c03ccc721b5a0.png"},{"id":105197348,"identity":"4bf109ec-ec36-4a17-a074-dbd76644bc10","added_by":"auto","created_at":"2026-03-23 10:29:10","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":4214178,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7181420/v1/a9e4f566-23b9-4788-93f0-321a18e2b56d.pdf"},{"id":105197226,"identity":"e7bdb29a-2c8a-4426-bdb6-e8535f943b3d","added_by":"auto","created_at":"2026-03-23 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10:27:29","extension":"docx","order_by":11,"title":"","display":"","copyAsset":false,"role":"supplement","size":533346,"visible":true,"origin":"","legend":"supplemental file1","description":"","filename":"supplementalfile1finalclinicalprotocolforclinicaltrial.docx","url":"https://assets-eu.researchsquare.com/files/rs-7181420/v1/42deb394730a4034c3aa56d0.docx"},{"id":105197053,"identity":"9e258bbb-8e0d-46f5-85dd-2a220c208c4e","added_by":"auto","created_at":"2026-03-23 10:27:36","extension":"docx","order_by":12,"title":"","display":"","copyAsset":false,"role":"supplement","size":102333,"visible":true,"origin":"","legend":"supplemental file9","description":"","filename":"supplementalfile9originalSAPforfollowupclinicaltrial.docx","url":"https://assets-eu.researchsquare.com/files/rs-7181420/v1/3774a03a8ec49c539919e063.docx"},{"id":105197247,"identity":"9f1adfd4-c7be-4069-a621-ffb24888ff84","added_by":"auto","created_at":"2026-03-23 10:28:27","extension":"docx","order_by":13,"title":"","display":"","copyAsset":false,"role":"supplement","size":332768,"visible":true,"origin":"","legend":"supplemental file4","description":"","filename":"supplementalfile4clinicalprotocolforfollowuptrial.docx","url":"https://assets-eu.researchsquare.com/files/rs-7181420/v1/4d1b948b6db574ebaa81cfc0.docx"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nThis work was supported by AMED (grant number JP17ek0109005) and Japan Tissue Engineering Co., Ltd, Gamagori, Japan. Y.O. reports a consulting fee and travel support. K.N. reports a consulting fee, payment for lectures and travel support. T.O. and M.I. are employee of Japan Tissue Engineering Co., Ltd. No other potential conflict of interest relevant to this article is reported.","formattedTitle":"Autologous cultivated oral mucosal epithelial cell sheets to treat stem cell-deficient vision loss: A multi-centre clinical trial","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eThe cornea is the transparent \u0026ldquo;window\u0026rdquo; at the front of the eye that transmits light into the eye and helps focus it on the retina. Its anterior surface is overlaid with a stratified, non-keratinised epithelium, which is constantly renewed by stem cells that reside in the basal epithelium of the limbus, a transitional zone between the cornea and adjacent conjunctiva.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Limbal epithelial stem cells are highly proliferative, expressing p63 and exhibiting strong holoclone-forming capabilities.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e If limbal stem cells are depleted by congenital disease or injury, however, an opacified and vascularised conjunctival pannus will envelop the cornea, severely disturbing vision.\u003csup\u003e\u003cspan additionalcitationids=\"CR5 CR6\" citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e This condition is called a limbal stem cell deficiency (LSCD). Although allogenic limbal transplantation has been used to treat LSCD, clinical outcomes are not always satisfactory because of postoperative complications that can include infectious keratitis or immunologic rejection.\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e To overcome these problems, cultivated autologous limbal stem cells, expanded into functional corneal epithelial cell sheets, have been successfully used for ocular surface reconstruction in patients with unilateral LSCD.\u003csup\u003e\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e Indeed, clinical trials have confirmed the efficacy and safety of cultivated limbal epithelial cell sheet transplantation,\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e with the cell sheet (named Nepic) now approved as a cellular and tissue-based product in Japan.\u003c/p\u003e\u003cp\u003eThis type of autologous treatment, however, is only applicable for a unilateral LSCD because a healthy epithelial tissue from the unaffected eye is required from which a limbal graft biopsy can be obtained. To overcome the need for healthy limbal tissue as a cell source, we developed cultivated oral mucosal epithelial cell sheet transplantation (COMET),\u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e which uses the patient\u0026rsquo;s oral mucosal epithelial cells as an alternative cell source. Accordingly, this method can be used to treat bilateral LSCD because the provision of healthy limbal epithelial cells is not required. After our initial report of COMET for LSCD, others reported encouraging results using similar techniques.\u003csup\u003e\u003cspan additionalcitationids=\"CR18 CR19 CR20 CR21\" citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e To date, however, all reports of COMET have limitations, either because of a retrospective single-centre study design or heterogeneity among transplanted cells due to the lack of evaluation under defined shipment criteria. Moreover, no clinical trial has been performed that adheres to Good Clinical Practice (GCP) stipulations within a defined clinical protocol and uses strict quality control for cell sheets fabricated in a Good Gene, Cellular, and Tissue-based Products Manufacturing Practice (GCTP) grade facility. Here, we report the outcome of a prospective, multicentre, government-controlled clinical trial using GCTP-derived cell sheets that confirms the efficacy and safety of COMET for LSCD.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003e\u003cstrong\u003eCharacteristics of the patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNine eyes of nine patients were judged by the investigators to match the inclusion and exclusion criteria, however, three of these were deemed to be ineligible by the Eligibility Judgement Committee based on LSCD staging. Of the remaining six patients, four were treated at Osaka University Hospital, with one each enrolled at Tohoku University Hospital and the University of Tokyo Hospital. Six consecutive patients were enrolled between August 2015 and September 2017 after providing written informed consent. The mean age of the patients, three male and three female, was 59\u0026plusmn;27 years at the time of enrolment (median age 66 years; range 26\u0026ndash;87 years). LSCD was caused by Stevens-Johnson syndrome (SJS) in two patients and mucous membrane pemphigoid (MMP) in two, with one suffering from aniridia. The other patient was idiopathic. Average preoperative visual acuity measured using Early Treatment of Diabetic Retinopathy Study (ETDRS) charts acuity was 2.18 \u0026plusmn; 0.66 logMAR. All six operated eyes were categorised as LSCD Stage III (Table 1), meaning that the entire cornea was covered by conjunctiva. For each patient, the cultivated oral mucosal epithelial cell sheets, derived from biopsies of their own buccal mucosa, met all defined shipment criteria (Table S4). The planned number of cases has been enrolled, and the clinical trials have been completed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEndpoints for efficacy and safety\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe corneal epithelium was successfully reconstructed, as the primary endpoint of the trial, one year postoperatively in six of six eyes (100%; 95% confidence interval [CI] 54.1\u0026ndash;100.0%), and was significantly higher than the 10%, clinically significant efficacy rate (P \u0026lt; 0.001, Fischer exact test).\u0026nbsp;At two years, a successful epithelial reconstruction was achieved in four of six eyes (66.7%; 95% CI, 22.3\u0026ndash;95.7%). Representative cases are shown in Figure 1. From this it can be seen that a patient without inflammation (C-3) had a clear cornea postoperatively, whereas a patient with early postoperative inflammation evidenced by severe hyperaemia (C-1) had a worse prognosis that included corneal opacification and neovascularisation. Preoperative and postoperative LSCD staging of all operated eyes is presented in Table 1. All six exhibited LSCD stage IA or IB at the one year postoperative timepoint, although two eyes had lapsed to stage IIB or III at 2 years. LSCD staging for the fellow eyes was mostly stable (Table S5).\u003c/p\u003e\n\u003cp\u003ePostoperative changes and grading of subjective symptoms are shown in Table 2 and Tables S6-S11. Foreign body sensation and photophobia improved in three operated eyes (50%) one and two years postoperatively. There were no major changes in other subjective symptoms. As shown in Table 2 and S12, decimal visual acuity improved in the same three operated eyes (50%), one and two years postoperatively. ETDRS visual acuity improved in three operated eyes (50%) at 1 year and two eyes (33%) at 2 years (Table 2 and S13). Quality of Life (QOL) scores, shown in Table S14, improved in five (83%) patients at year one, and in three (50%) patients two years postoperatively.\u0026nbsp;Corneal opacification improved in three (50%) eyes, one and two years postoperatively (Table 2 and S15). Corneal neovascularisation improved in three (50%) operated eyes at one and two years (Table 2 and S16). No significant changes in symblepharon (Table 2 and S17), a partial or complete adhesion of the palpebral conjunctiva of the eyelid to the bulbar conjunctiva of the eyeball, were noted throughout the follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003c/strong\u003eWith regards to safety endpoints, superficial punctate keratitis was observed in all operated and fellow eyes (100%) preoperatively and postoperatively. Corneal epithelial defects were not seen in any of the operated or fellow eyes preoperatively, but after surgery it was observed in five operated eyes (83%) and three fellow eyes (50%). Keratinisation was observed in one fellow eye (17%). Conjunctival hyperaemia was a feature of all eyes preoperatively and was observed in all operated eyes and five of six fellow eyes (83%), postoperatively. Infectious keratitis or endophthalmitis were not observed. We observed three serious adverse events, as defined by the clinical protocols (Supplemental Files), which required hospitalisation for treatment. These comprised one case of cellulitis (16.7%), one of dacryocystitis (16.7%) and another of cataract in the unoperated eye (16.7%). All adverse events (Tables S18 to S21) were treated successfully and did not result in any residual effects. A causal relationship with the COMET surgery or cell sheets was ruled out for all adverse events.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eHere, we describe the world\u0026rsquo;s first government-controlled clinical trial that follows a prospective multicentre clinical study design (Supplementary Files) using cultivated oral mucosal epithelial cell sheets. The sheets were generated in a GCTP-grade facility, with strict quality control oversight, and were used in adherence to GCP guidelines and a defined clinical protocol. Evaluation of the primary endpoints was objectively conducted by third-party cornea specialists using anonymously and randomly provided clinical photographs, without any accompanying information. As a primary efficacy endpoint, the corneal epithelium was successfully reconstructed in 100% and 66.7% of eyes at postoperative years one and two, respectively. Visual acuity improved significantly in 50% of treated eyes at one and two years, as did corneal opacification and neovascularisation. Importantly, we did not experience any clinically significant adverse events. Data were reviewed by the Ministry of Health, Labor and Welfare in Japan, after which the autologous cultivated oral mucosal epithelial cell sheet was approved as a Cellular and Tissue-based product, called \u0026ldquo;Ocural\u0026rdquo;, in Japan. This represents the world\u0026rsquo;s first approval of a cultivated oral mucosal epithelial cell sheet for use in eye surgery.\u003c/p\u003e\n\u003cp\u003eOur primary endpoint measure, a corneal epithelial reconstruction success rate of 100% at postoperative year one and 67% at postoperative year two is higher than the clinically significant success rate of 10% achieved by conventional allogenic limbal transplantation. A related clinical study conducted by us (Supplementary Appendix) uncovered a 100% success rate for COMET outcomes in 26 LSCD patients, although a different clinical grading system was used in that research because the global consensus for LSCD classification\u003csup\u003e4\u003c/sup\u003e had not yet been established. The success rate reported here, we note, is also similar to the ocular surface reconstruction success rate reported in previous review articles describing COMET, as shown in Table 3,\u003csup\u003e23-26\u003c/sup\u003e and to the 60-85% success following cultivated limbal epithelial cell sheet transplantation.\u003csup\u003e13,27,28\u003c/sup\u003e A significant feature of the current study is that the success rate was evaluated by third-party endpoint evaluators who were provided with slit-lamp photographs anonymously and in random order.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTwo eyes of two patients in this trial were complicated by early postoperative inflammation (Figure 1). Previous investigations have also shown that failed cases of cultivated limbal epithelial cell sheet transplantation could be accompanied by severe early postoperative inflammation and subsequent conjunctival invasion onto the central cornea.\u003csup\u003e13\u003c/sup\u003e Therefore, postoperative inflammation after surgeries of these types needs to be carefully monitored and well managed if a good long-term prognosis is to be achieved. However, achieving complete control of inflammation remains a challenge, as causative diseases such as SJS or MMP often provoke severe inflammation that is resistant to current therapeutic options.\u003c/p\u003e\n\u003cp\u003eThe improvement of visual acuity in 50% of cases reported here is judged to be a highly positive outcome when we remember that we only performed cultivated epithelial cell sheet transplantation, and visual acuity can be negatively influenced by a host of unrelated ocular disorders such as corneal stromal opacification, cataract, glaucoma and/or retinal pathology. Our study of the clinical outcomes of COMET conducted prior to the creation of the global consensus of LSCD by Deng and associates on behalf of The International LSCD Working Group,\u003csup\u003e4\u003c/sup\u003e likewise showed improved visual acuity in 50% of cases one year postoperatively, and 63.6% of cases at postoperative year two (including those receiving keratoplasty for corneal stromal opacification). Corneal opacification and neovascularisation improved in 50% cases in our clinical trial, reported here, with the rate similar to that seen in our related clinical study of 22 patients with LSCD (Supplementary Appendix).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWith regards to safety endpoints, we experienced three serious adverse events defined by the clinical protocol in this clinical trial at postoperative year two (five events occurred our pre-global consensus clinical study (Supplementary Appendix)). We judge that none of the serious adverse events in the clinical trial were caused by the tissue collection or investigational product. Some of the serious adverse events in the clinical study were felt to be related to the treatment but all were successfully treated without permanent damage (Supplementary Appendix). Ocular hypertension occurred in 16.7% of cases (n = 1 of 6) in the clinical trial and 40.9% of cases (n = 9 of 22) in the clinical study, but all eyes were adequately treated without ongoing symptoms. Immunological rejection and infectious keratitis were not seen.\u003c/p\u003e\n\u003cp\u003eA limitation of our studies, including both clinical trials with 6 patients and clinical study with 22 cases, is the relatively small number of total cases. This limits the generalizability of our findings and precludes definitive conclusions regarding the direct comparisons with other treatments for LSCD.\u003c/p\u003e\n\u003cp\u003eWe recently published the results of a first-in-human interventional study using human induced pluripotent stem-cell-derived corneal epithelium involving four patients with LSCD.\u003csup\u003e29\u003c/sup\u003e Although the results were positive, only a small number of patients were studied, and confirmation from a larger multicentre clinical trial is required to adopt this approach. As a current alternative, autologous COMET, described here, is a safe and effective treatment for LSCD, as established in this government-controlled clinical trial of a newly approved Cellular and Tissue-based product for ocular regenerative medicine.\u0026nbsp;\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design and trial oversight\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe conducted a prospective, multicentre, open-label, uncontrolled, single-arm clinical trial to establish the efficacy and safety of graft surgery employing autologous cultivated oral mucosal epithelial cell sheets (the investigational product). Detailed clinical protocols are provided in the supplemental files. The initial physician-oriented clinical trial had a postoperative follow-up period of one year, extended to two years for in the same cohort of patients via an additional one-year follow-up. In the initial trial, patient monitoring comprised an observation period before surgery and a follow-up period postoperatively (Tables S1 to S3). The trial protocol was approved by the Institutional Review Boards of each participating institute (Osaka University Hospital, Tohoku University Hospital, University of Tokyo Hospital) and by the Ministry of Health, Labor and Welfare of Japan. The trial was conducted according to tenets of the Declaration of Helsinki and was registered as UMIN000018662.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatients and endpoints\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInclusion criteria for the clinical trial were as follows: 1) Patients diagnosed with stage III LSCD \u003csup\u003e4\u003c/sup\u003e; 2) a lack of extensive oral mucosal scarring and the presence of healthy oral mucosal tissue for harvest; 3) patients \u0026ge;20-years-old at the time of informed consent. Detailed exclusion criteria are described in the clinical protocols (Supplemental File).\u003c/p\u003e\n\u003cp\u003eThe trial\u0026rsquo;s primary endpoint was the success rate of corneal epithelial reconstruction (%) one and two years after transplantation of the oral mucosal epithelial cell sheet as the investigational device. LSCD staging was evaluated according to the criteria agreed by global consensus,\u003csup\u003e\u0026nbsp;4\u003c/sup\u003e not only in the operated eye but the fellow eye, too. After surgery, if the operated eye was evaluated as being LSCD stage IA to C, the surgery was considered to be a success. LSCD diagnosis and staging was initially conducted by on-site corneal specialists aided by slit-lamp examination, including fluorescein staining. It was finally determined by the trial\u0026rsquo;s Eligibility Judgment Committee and Effect Assessment Committee using slit-lamp photographs, including fluorescein staining. Both committees were composed of 2-3 third-party cornea specialists, who were provided with slit-lamp photographs anonymously and in random order. Two-sided 95% confidence intervals (CI) for the primary endpoint were calculated using the Clopper\u0026ndash;Pearson method. Success rates one year postoperatively were determined using an exact binomial test at a two-sided alpha level of 5% to examine the null hypothesis that the success rate would be 10%. (Supplemental File). Secondary endpoints for efficacy were as follows: 1) LSCD stage after transplantation of the investigational product; 2) Subjective symptoms; 3) Corrected visual acuity using a decimal visual acuity chart and an ETDRS chart; 4) Quality of life (QOL) as evaluated by the 25-item National Eye Institute Visual Function Questionnaire (NEI-VFQ25); 5) Severity of corneal opacity;\u003csup\u003e30\u003c/sup\u003e 6) Severity of corneal neovascularisation;\u003csup\u003e30\u003c/sup\u003e 7) Severity of symblepharon.\u003csup\u003e30\u003c/sup\u003e We also evaluated whether or not additional treatment to improve visual acuity was indicated at one-year, and whether or not this contributed to the restoration of the corneal surface at the two-year juncture in subjects who received additional treatment. We also evaluated the untreated contralateral eye for LSCD stage, subjective symptoms, corrected visual acuity, severity of corneal opacity, corneal neovascularisation and symblepharon. Visual acuity is presented as logMAR (logarithm of the minimum angle of resolution) values, with improvements of more than two lines regarded as significant. Improvement of one or more grades for corneal opacification, neovascularisation and symblepharon were considered significant. The occurrence of superficial punctate keratopathy, the presence of corneal epithelial defects, corneal keratinisation, conjunctival hyperaemia, infectious keratitis and endophthalmitis up to one-year were assessed as safety criteria. Adverse events and malfunctions of the investigational device (i.e. the COMET cell sheet) were also recorded and converted to standard terms using the Medical Dictionary for Regulatory Activities (MedDRA) /J Ver21.0. The analysis methods are described in detail in the study analysis plan. (Supplemental files) No important changes were made after the trial commenced.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCell sheet fabrication and quality control\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor each patient an oral mucosal tissue biopsy, approximately 50 mm\u003csup\u003e2\u003c/sup\u003e in size, was obtained from the buccal mucosa, after which cells were dissociated and cultivated on temperature responsive culture surfaces as previously reported. (Figure 2)\u003csup\u003e13,14,31\u0026nbsp;\u003c/sup\u003eVirus validated, lethally irradiated 3T3-J2 cells from an established working cell bank were used as feeder cells. All cell sheets were fabricated in a GMP-grade facility managed by Japan Tissue Engineering Co. Ltd (Gamagori, Japan) under established standard operating procedures (SOPs), guided and recorded under a process management system. Cell sheets were evaluated using defined shipment criteria before transplantation, and only those that met the criteria were used for transplantation. Cell sheets were transported from the GCTP-grade facility to transplantation facilities using a specially designed container.\u003csup\u003e32\u0026nbsp;\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTransplantation and post-operative care\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA single expanded oral mucosal epithelial cell sheet was transplanted onto each of the patients diseased eyes as described in detail elsewhere.\u003csup\u003e13,14\u0026nbsp;\u003c/sup\u003eBriefly, superficial conjunctival scar tissue that enveloped the corneal surfaces was dissected away to expose bare corneal stroma up to 3 mm outside the limbus. The cell sheet, which had been lifted from its temperature-responsive culture dish, was then grafted directly onto the corneal stroma and a therapeutic soft contact lens placed on the eye for protection. Postoperative local medication included topical antibiotics (0.5% cefmenoxime) and corticosteroids (0.1% betamethasone) as eye drops four times a day, along with betamethasone and fradiomycin ointment once a day. Betamethasone eye drops were switched to 0.1% fluorometholone eye drops 3\u0026ndash;6 months after surgery depending on the level of inflammation seen in individual eyes. Systemic corticosteroid was administered as 125 mg methylprednisolone on the day of surgery, followed by 2 mg of betamethasone for two days and 1 mg of betamethasone for 1 month with tapering. We administered systemic corticosteroid only in cases where the ocular surface inflammation could not be suppressed with corticosteroid eye drops. Some patients experienced severe dry eye, and self-administered artificial tears.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eCOMPETING INTEREST\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by AMED (grant number JP17ek0109005) and Japan Tissue Engineering Co., Ltd, Gamagori, Japan. Y.O. reports a consulting fee and travel support. K.N. reports a consulting fee, payment for lectures and travel support. T.O. and M.I. are employee of Japan Tissue Engineering Co., Ltd. No other potential conflict of interest relevant to this article is reported.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDATA AVAILABILITY\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll deidentified participant data, including individual participant data and the trial protocol are available in the appendix and will be available with no end date.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCotsarelis, G., Cheng, S. Z., Dong, G., Sun, T. T. \u0026amp; Lavker, R. M. Existence of slow-cycling limbal epithelial basal cells that can be preferentially stimulated to proliferate: implications on epithelial stem cells. \u003cem\u003eCell\u003c/em\u003e \u003cstrong\u003e57\u003c/strong\u003e, 201\u0026ndash;209 (1989). https://doi.org/10.1016/0092-8674(89)90958-6\u003c/li\u003e\n\u003cli\u003ePellegrini, G. et al. Location and clonal analysis of stem cells and their differentiated progeny in the human ocular surface. \u003cem\u003eJ. Cell Biol.\u003c/em\u003e \u003cstrong\u003e145\u003c/strong\u003e, 769\u0026ndash;782.1 https://doi.org/10.1083/jcb.145.4.769\u003c/li\u003e\n\u003cli\u003ePellegrini, G. et al. p63 identifies keratinocyte stem cells. \u003cem\u003eProc. Natl Acad. Sci. U. S. A.\u003c/em\u003e \u003cstrong\u003e98\u003c/strong\u003e, 3156\u0026ndash;3161 (2001). https://doi.org/10.1073/pnas.061032098 \u003c/li\u003e\n\u003cli\u003eDeng, S. X. et al. Global consensus on definition, classification, diagnosis, and staging of limbal stem cell deficiency. \u003cem\u003eCornea\u003c/em\u003e \u003cstrong\u003e38\u003c/strong\u003e, 364\u0026ndash;375 (2019). https://doi.org/10.1097/ico.0000000000001820 \u003c/li\u003e\n\u003cli\u003eOie, Y. \u0026amp; Nishida, K. Corneal regenerative medicine. \u003cem\u003eRegen. Ther.\u003c/em\u003e \u003cstrong\u003e5\u003c/strong\u003e, 40-45 (2016). https://doi.org/10.1016/j.reth.2016.06.002 \u003c/li\u003e\n\u003cli\u003eOie, Y. \u0026amp; Nishida, K. Evaluation of corneal neovascularization using optical coherence tomography angiography in patients with limbal stem cell deficiency. \u003cem\u003eCornea\u003c/em\u003e \u003cstrong\u003e36\u003c/strong\u003e, S72-S75 (2017). https://doi.org/10.1097/ico.0000000000001382 \u003c/li\u003e\n\u003cli\u003eKiritoshi, S. et al. Anterior segment optical coherence tomography angiography in patients following cultivated oral mucosal epithelial transplantation. \u003cem\u003eAm. J. Ophthalmol.\u003c/em\u003e \u003cstrong\u003e208\u003c/strong\u003e, 242-250 (2019). https://doi.org/10.1016/j.ajo.2019.08.006 \u003c/li\u003e\n\u003cli\u003eTsubota, K. et al. Treatment of severe ocular-surface disorders with corneal epithelial stem-cell transplantation. \u003cem\u003eN. Engl. J. Med.\u003c/em\u003e \u003cstrong\u003e340\u003c/strong\u003e, 1697\u0026ndash;1703 (1999). https://doi.org/10.1056/nejm199906033402201 \u003c/li\u003e\n\u003cli\u003eIlari, L. \u0026amp; Daya, S. M. Long-term outcomes of keratolimbal allograft for the treatment of severe ocular surface disorders. \u003cem\u003eOphthalmology\u003c/em\u003e \u003cstrong\u003e109\u003c/strong\u003e, 1278\u0026ndash;1284 (2002). https://doi.org/10.1016/s0161-6420(02)01081-3\u003c/li\u003e\n\u003cli\u003ePellegrini, G. et al. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. \u003cem\u003eLancet\u003c/em\u003e \u003cstrong\u003e349\u003c/strong\u003e, 990\u0026ndash;993 (1997). https://doi.org/10.1016/s0140-6736(96)11188-0 \u003c/li\u003e\n\u003cli\u003eRama, P. et al. Limbal stem-cell therapy and long-term corneal regeneration. \u003cem\u003eN. Engl. J. Med.\u003c/em\u003e \u003cstrong\u003e363\u003c/strong\u003e, 147\u0026ndash;155 (2010). https://doi.org/10.1056/nejmoa0905955 \u003c/li\u003e\n\u003cli\u003eJurkunas, U.V. et al. Cultivated autologous limbal epithelial cell (CALEC) transplantation for limbal stem cell deficiency: a phase I/II clinical trial of the first xenobiotic-free, serum-free, antibiotic-free manufacturing protocol developed in the US. Nat. Commun. \u003cstrong\u003e16\u003c/strong\u003e, 1607 (2025). https://doi.org/10.1038/s41467-025-56461-1\u003c/li\u003e\n\u003cli\u003eOie, Y. et al. Clinical trial of autologous cultivated limbal epithelial cell sheet transplantation for patients with limbal stem cell deficiency. \u003cem\u003eOphthalmology\u003c/em\u003e \u003cstrong\u003e130\u003c/strong\u003e, 608\u0026ndash;614 (2023). https://doi.org/10.1016/j.ophtha.2023.01.016 \u003c/li\u003e\n\u003cli\u003eNishida, K. et al. Corneal reconstruction with tissue-engineered cell sheets composed of autologous oral mucosal epithelium. \u003cem\u003eN. Engl. J. Med.\u003c/em\u003e \u003cstrong\u003e351\u003c/strong\u003e, 1187\u0026ndash;1196 (2004). https://doi.org/10.1056/nejmoa040455 \u003c/li\u003e\n\u003cli\u003eSoma, T. et al. Maintenance and distribution of epithelial stem/progenitor cells after corneal reconstruction using oral mucosal epithelial cell sheets. \u003cem\u003ePLOS One\u003c/em\u003e \u003cstrong\u003e9\u003c/strong\u003e, e110987 (2014). https://doi.org/10.1371/journal.pone.0110987 \u003c/li\u003e\n\u003cli\u003eOie, Y. \u0026amp; Nishida, K. Translational research on ocular surface reconstruction using oral mucosal epithelial cell sheets. \u003cem\u003eCornea\u003c/em\u003e \u003cstrong\u003e33\u003c/strong\u003e(Suppl 11), S47-S52 (2014). https://doi.org/10.1097/ico.0000000000000232 \u003c/li\u003e\n\u003cli\u003eNakamura, T. et al. Transplantation of cultivated autologous oral mucosal epithelial cells in patients with severe ocular surface disorders. \u003cem\u003eBr. J. Ophthalmol.\u003c/em\u003e \u003cstrong\u003e88\u003c/strong\u003e, 1280\u0026ndash;1284 (2004). https://doi.org/10.1136/bjo.2003.038497 \u003c/li\u003e\n\u003cli\u003eInatomi, T., Nakamura, T., Koizumi, N., Sotozono, C. \u0026amp; Kinoshita, S. Current concepts and challenges in ocular surface reconstruction using cultivated mucosal epithelial transplantation. \u003cem\u003eCornea\u003c/em\u003e \u003cstrong\u003e24\u003c/strong\u003e(8)(Suppl), S32\u0026ndash;S38 (2005). https://doi.org/10.1097/01.ico.0000178739.37083.2c\u003c/li\u003e\n\u003cli\u003eMa, D. H. et al. Transplantation of cultivated oral mucosal epithelial cells for severe corneal burn. \u003cem\u003eEye (Lond.)\u003c/em\u003e \u003cstrong\u003e23\u003c/strong\u003e, 1442\u0026ndash;1450 (2009). https://doi.org/10.1038/eye.2009.60 \u003c/li\u003e\n\u003cli\u003eNakamura, T., Takeda, K., Inatomi, T., Sotozono, C. \u0026amp; Kinoshita, S. Long-term results of autologous cultivated oral mucosal epithelial transplantation in the scar phase of severe ocular surface disorders. \u003cem\u003eBr. J. Ophthalmol.\u003c/em\u003e \u003cstrong\u003e95\u003c/strong\u003e, 942\u0026ndash;946 (2011). https://doi.org/10.1136/bjo.2010.188714 \u003c/li\u003e\n\u003cli\u003eSatake, Y., Higa, K., Tsubota, K. \u0026amp; Shimazaki, J. Long-term outcome of cultivated oral mucosal epithelial sheet transplantation in treatment of total limbal stem cell deficiency. \u003cem\u003eOphthalmology\u003c/em\u003e \u003cstrong\u003e118\u003c/strong\u003e, 1524\u0026ndash;1530 (2011). https://doi.org/10.1016/j.ophtha.2011.01.039 \u003c/li\u003e\n\u003cli\u003eBurillon, C. et al. Cultured autologous oral mucosal epithelial cell sheet (CAOMECS) transplantation for the treatment of corneal limbal epithelial stem cell deficiency. \u003cem\u003eInvest. Ophthalmol. Vis. Sci.\u003c/em\u003e \u003cstrong\u003e53\u003c/strong\u003e, 1325\u0026ndash;1331 (2012). https://doi.org/10.1167/iovs.11-7744 \u003c/li\u003e\n\u003cli\u003eUtheim, T. P. Concise review: transplantation of cultured oral mucosal epithelial cells for treating limbal stem cell deficiency-current status and future perspectives. \u003cem\u003eStem Cells\u003c/em\u003e \u003cstrong\u003e33\u003c/strong\u003e, 1685\u0026ndash;1695 (2015). https://doi.org/10.1002/stem.1999 \u003c/li\u003e\n\u003cli\u003eOie, Y., Komoto, S. \u0026amp; Kawasaki, R. Systematic review of clinical research on regenerative medicine for the cornea. \u003cem\u003eJpn. J. Ophthalmol.\u003c/em\u003e \u003cstrong\u003e65\u003c/strong\u003e, 169\u0026ndash;183 (2021). https://doi.org/10.1007/s10384-021-00821-z \u003c/li\u003e\n\u003cli\u003eCabral, J. V., Jackson, C. J., Utheim, T. P. \u0026amp; Jirsova, K. Ex vivo cultivated oral mucosal epithelial cell transplantation for limbal stem cell deficiency: a review. \u003cem\u003eStem Cell Res. Ther.\u003c/em\u003e \u003cstrong\u003e11\u003c/strong\u003e, 301 (2020). https://doi.org/10.1186/s13287-020-01783-8 \u003c/li\u003e\n\u003cli\u003eFigueiredo, F. C. et al. A systematic review of cellular therapies for the treatment of limbal stem cell deficiency affecting one or both eyes. \u003cem\u003eOcul. Surf.\u003c/em\u003e \u003cstrong\u003e20\u003c/strong\u003e, 48\u0026ndash;61 (2021). https://doi.org/10.1016/j.jtos.2020.12.008 \u003c/li\u003e\n\u003cli\u003eLe, Q., Chauhan, T., Yung, M., Tseng, C. H. \u0026amp; Deng, S. X. Outcomes of limbal stem cell transplant: A meta-analysis. \u003cem\u003eJAMA Ophthalmol.\u003c/em\u003e \u003cstrong\u003e138\u003c/strong\u003e, 660\u0026ndash;670 (2020). https://doi.org/10.1001/jamaophthalmol.2020.1120 \u003c/li\u003e\n\u003cli\u003eZhao, Y. \u0026amp; Ma, L. Systematic review and meta-analysis on transplantation of ex vivo cultivated limbal epithelial stem cell on amniotic membrane in limbal stem cell deficiency. \u003cem\u003eCornea\u003c/em\u003e \u003cstrong\u003e34\u003c/strong\u003e, 592\u0026ndash;600 (2015). https://doi.org/10.1097/ico.0000000000000398 \u003c/li\u003e\n\u003cli\u003eSoma, T. et al. Induced pluripotent stem-cell-derived corneal epithelium for transplant surgery: a single-arm, open-label, first-in-human interventional study in Japan. \u003cem\u003eLancet\u003c/em\u003e \u003cstrong\u003e404\u003c/strong\u003e, 1929\u0026ndash;1939 (2024). https://doi.org/10.1016/s0140-6736(24)01764-1 \u003c/li\u003e\n\u003cli\u003eSotozono, C. et al. New grading system for the evaluation of chronic ocular manifestations in patients with Stevens-Johnson syndrome. \u003cem\u003eOphthalmology\u003c/em\u003e \u003cstrong\u003e114\u003c/strong\u003e, 1294\u0026ndash;1302 (2007). https://doi.org/10.1016/j.ophtha.2006.10.029 \u003c/li\u003e\n\u003cli\u003eNishida, K. et al. Functional bioengineered corneal epithelial sheet grafts from corneal stem cells expanded ex vivo on a temperature-responsive cell culture surface. \u003cem\u003eTransplantation\u003c/em\u003e \u003cstrong\u003e77\u003c/strong\u003e, 379\u0026ndash;385 (2004). https://doi.org/10.1097/01.tp.0000110320.45678.30 \u003c/li\u003e\n\u003cli\u003eOie, Y. et al. Development of a cell sheet transportation technique for regenerative medicine. \u003cem\u003eTissue Eng. Part C Methods\u003c/em\u003e \u003cstrong\u003e20\u003c/strong\u003e, 373\u0026ndash;382 (2014). https://doi.org/10.1089/ten.tec.2013.0266\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. LSCD staging of operated eyes following cultivated oral mucosal epithelial cell sheets transplantation\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"972\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003ePatient anonymisation number\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003eCausative disease\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003ePreoperative stage\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e2 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e4 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e12 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e24 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e52 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003e78 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003e104 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003eA-3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e57\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003eCongenital aniridia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003eB-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003eSJS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003eC-1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003eSJS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eIIB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003eC-2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e80\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eF\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003eMMP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eIB\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003eC-3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003eIdiopathic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 118px;\"\u003e\n \u003cp\u003eC-5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e87\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 65px;\"\u003e\n \u003cp\u003eM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 121px;\"\u003e\n \u003cp\u003eMMP\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 106px;\"\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 72px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 74px;\"\u003e\n \u003cp\u003eIA\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eLSCD: limbal stem cell deficiency, SJS: Stevens-Johnson syndromed, MMP: mucous membrane pemphigoid\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2. Postoperative changes of subjective symptoms, visual acuity, corneal opacification, corneal neovascularisation, and symblepharon\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eEye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eChange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003eOcular pain\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eForeign body sensation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eLacrimation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003ePhotophobia\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eDryness\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003eDiscomfort\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e52 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e104 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e52 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e104 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e52 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e104 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e52 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e104 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e52 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e104 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e52 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e104 weeks\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eOperated eye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eUnchanged\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e4 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e4 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e5 (83%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e5 (83%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e4 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eDeteriorated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003eFellow eye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eUnchanged\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e4 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e6 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e4 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e4 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e5 (83%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e5 (83%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e4 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e5 (83%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 123px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003eDeteriorated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"\" width=\"976\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eEye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eChange\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 149px;\"\u003e\n \u003cp\u003eDecimal visual acuity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eETDRS visual acuity\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eCorneal opacification\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eCorneal neovascularisation\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003eSymblepharon\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e52\u003c/p\u003e\n \u003cp\u003eweeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e104\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eweeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e52\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eweeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e104\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eweeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e52\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eweeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e104\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eweeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e52\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eweeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e104\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eweeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e52\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eweeks\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e104\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eweeks\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eOperated eye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eUnchanged\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e6 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e6 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eDeteriorated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003eFellow eye\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eImproved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eUnchanged\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e2 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e4 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e5 (83%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e5 (83%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e5 (83%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e6 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 129px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eDeteriorated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e4 (67%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e3 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e1 (17%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 80px;\"\u003e\n \u003cp\u003e0 (0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eETDRS: Early Treatment of Diabetic Retinopathy Study\u0026nbsp;\u003cbr clear=\"all\"\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3. Comparison of clinical outcomes between the current clinical trial and meta-analysis or systematic review\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"1021\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 211px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 149px;\"\u003e\n \u003cp\u003eCurrent clinical trial\u003c/p\u003e\n \u003cp\u003e(N=6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;Utheim TP.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Stem Cells 2015 \u003csup\u003e23\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003eOie Y et al.\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eJpn J Ophthalmol 2021 \u003csup\u003e24\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003eCabral JV et al.\u003c/p\u003e\n \u003cp\u003eStem Cell Res Ther 2020 \u003csup\u003e25\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003eFigueiredo FC et al.\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;Ocul Surf 2021 \u003csup\u003e26\u003c/sup\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 211px;\"\u003e\n \u003cp\u003eCorneal epithelium reconstruction\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 149px;\"\u003e\n \u003cp\u003e100% (1 year)\u003c/p\u003e\n \u003cp\u003e66.7% (2 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;72%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e66.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003e70.8%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e\u0026nbsp;71.4%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 211px;\"\u003e\n \u003cp\u003eVisual recovery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 149px;\"\u003e\n \u003cp\u003e50% (1 year)\u003c/p\u003e\n \u003cp\u003e50% (2 years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;68%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e66.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003e63.5%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 211px;\"\u003e\n \u003cp\u003eOcular hypertension\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 149px;\"\u003e\n \u003cp\u003e16.7%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;9%\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(including glaucoma)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e8.1%\u003c/p\u003e\n \u003cp\u003e(including glaucoma)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 211px;\"\u003e\n \u003cp\u003eImmunological rejection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 149px;\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 211px;\"\u003e\n \u003cp\u003eInfectious keratitis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 149px;\"\u003e\n \u003cp\u003e0%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003e\u0026nbsp;1.6%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e5.3%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 179px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 164px;\"\u003e\n \u003cp\u003e\u0026nbsp;-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7181420/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7181420/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eLimbal epithelial stem cells located at the corneal periphery are essential for maintaining the integrity of the corneal epithelium. Their depletion, known as a limbal stem cell deficiency (LSCD), can cause severe vision loss. Cultivated oral mucosal epithelial cell sheet transplantation (COMET) offers a promising treatment for LSCD. Here, six eyes of six patients underwent COMET in a prospective, multi-centre, government-controlled clinical trial. Only Good Gene, Cellular and Tissue-based Products Manufacturing Practice-compliant cell sheets were used, with follow-up for two years. The primary endpoint, corneal epithelial reconstruction, was successfully achieved in 100% of eyes at one year and 67% at two years. Visual acuity improved in 50% of eyes at both the one and two year examinations, with corneal opacification diminished in 33% and 50% of eyes, respectively. No clinically significant adverse events occurred throughout the whole follow-up period and the efficacy and safety of COMET was thus confirmed. The cell sheet, \u0026ldquo;Ocural\u0026rdquo;, is now approved as a Cellular and Tissue-Based Product, the world\u0026rsquo;s first regenerative medicine product for COMET.\u003c/p\u003e\u003cp\u003eTrial registration numbers: UMIN000018662 (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000021510\u003c/span\u003e\u003cspan address=\"https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000021510\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) registered on 13 August 2015.\u003c/p\u003e","manuscriptTitle":"Autologous cultivated oral mucosal epithelial cell sheets to treat stem cell-deficient vision loss: A multi-centre clinical trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-23 10:24:18","doi":"10.21203/rs.3.rs-7181420/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"5f72e108-2218-4601-956c-33f16560e3c8","owner":[],"postedDate":"March 23rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":54505042,"name":"Health sciences/Health care/Therapeutics/Stem-cell therapies"},{"id":54505043,"name":"Health sciences/Diseases/Eye diseases/Corneal diseases"}],"tags":[],"updatedAt":"2026-03-23T10:24:18+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-23 10:24:18","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7181420","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7181420","identity":"rs-7181420","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}