Three-Dimensional Reflectivity Analysis of Corneal Layers Following Cultivated Epithelial Transplantation using Optical Coherence Tomography Short title: Corneal reflectivity analysis following cultivated epithelial transplantation

Three-Dimensional Reflectivity Analysis of Corneal Layers Following Cultivated Epithelial Transplantation using Optical Coherence Tomography Short title: Corneal reflectivity analysis following cultivated epithelial transplantation | 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 Three-Dimensional Reflectivity Analysis of Corneal Layers Following Cultivated Epithelial Transplantation using Optical Coherence Tomography Short title: Corneal reflectivity analysis following cultivated epithelial transplantation Rintaro Ogino, Yurina Mori-Ogiwara, Taiyo Shijo, Hirotsugu Kasamatu, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7406641/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Limbal stem cell deficiency (LSCD) is a debilitating condition that impairs corneal transparency and visual function due to damage of the limbal niche. Traditional treatments often fall short in bilateral cases or severe opacity. Cultivated oral mucosal epithelial transplantation (COMET) has recently emerged as a novel regenerative approach to restore the ocular surface in LSCD. Here we show that COMET leads to significant improvements in visual acuity and reduction of corneal surface irregularities. Using anterior segment optical coherence tomography (OCT), we evaluated corneal reflectivity in the epithelial, stromal, and endothelial layers over time. We found early reduction in epithelial opacity, while stromal reflectivity showed a persistent correlation with visual outcomes. Higher-order aberrations also decreased postoperatively and were significantly associated with better vision. These findings demonstrate the clinical potential of COMET to improve both structural and optical quality of the cornea and highlight the value of quantitative OCT imaging in evaluating therapeutic response. This study provides new insight into visual rehabilitation mechanisms in patients with severe LSCD and supports broader application of cultivated epithelial cell therapies in ocular surface reconstruction. Health sciences/Diseases Health sciences/Medical research Limbal stem cell deficiency stromal opacity higher order aberration anterior segment optical coherence tomography cultivated epithelial transplantation Figures Figure 1 Figure 2 Figure 3 Introduction Limbal stem cell deficiency (LSCD) is a severe ocular surface disorder caused by complete loss of limbal stem cells. These cells are essential for maintaining the integrity of the corneal epithelium and for preserving the barrier function of the limbus 1 . Their loss results in conjunctival ingrowth over the corneal surface, leading to marked opacification and substantial visual impairment. Currently available therapeutic strategies include autologous limbal transplantation (AULT) and keratolimbal allograft (KLAL). While AULT avoids systemic immunosuppression and carries a relatively low risk of graft rejection, it is only feasible in unilateral cases. In contrast, KLAL can be applied to bilateral disease but is limited by its high risk of rejection and the requirement for long-term immunosuppressive therapy 2 . In 1997, Pellegrini et al. reported a novel procedure utilizing ex vivo cultivated autologous limbal epithelial cells for ocular surface reconstruction 3 . In this technique, epithelial cells taken from the limbus of the healthy eye are cultured to generate cohesive sheets of authentic corneal epithelium for transplantation. More recently, Nepic®, an autologous cultured corneal epithelial product, was launched in March 2020 for the management of unilateral LSCD. Nevertheless, LSCD frequently develops bilaterally. Its underlying causes include genetic (e.g., aniridia), acquired (e.g., ocular cicatricial pemphigoid [OCP], Stevens–Johnson syndrome [SJS], trauma, or chemical burns), or idiopathic. In such cases, healthy donor limbal tissue is usually absent or insufficient for autologous transplantation. Oral mucosal epithelial cells has emerged as a promising alternative source because it shares structural and functional similarities with corneal epithelium 4 . In June 2021, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan approved Ocural ® , the first ex vivo cultivated oral mucosal epithelial transplantation (COMET) product for the treatment of bilateral LSCD. Maintaining corneal transparency is crucial for visual function, yet stromal opacity in LSCD is difficult to assess accurately, particularly when epithelial opacification is severe, using slit-lamp examination alone. Anterior segment optical coherence tomography (AS-OCT), which employs 1310-nm infrared light, enables non-invasive, reproducible, and objective quantification of corneal reflectivity, even in markedly opaque corneas. The aim of the present study was to analyze temporal changes in corneal reflectivity following COMET with Ocural ® and to determine how these changes are associated with stromal opacity and postoperative visual outcomes. Methods The study followed the principles of the Declaration of Helsinki and was approved by Institutional Review Board of Tokyo Dental College Ichikawa General Hospital (Approval number: I23-54, Approval date: October 13th, 2021). Patient data were anonymized prior to access and/or analysis. Informed consent has been obtained from all patients and/or legal guardians. In this prospective study, 14 eyes of 12 patients with LSCD undergoing cultivated epithelial transplantation at Tokyo Dental College Ichikawa General Hospital from April 2022 to June 2024 were included for analysis. LSCD was diagnosed, based on the international expert consensus on LSCD criteria 5 . In this study, all patients with Grade 3 LSCD underwent cultivated oral mucosal epithelial transplantation using Ocural ® (JTEC, Aichi, Japan). Surgical methods COMET surgeries were performed by one of the two experienced surgeons (T.Y. and D.T.). Briefly, an oral mucosal biopsy specimen from buccal mucosa (5 mm × 20 mm) was obtained from the subjects, and sent to JTEC laboratory to produce cultivated epithelial sheet. After 4-weeks of culture, sheets were sent back to Tokyo Dental College Ichikawa General Hospital and used for epithelial transplantation. After 360˚conjunctival peritomy, fibrovascular tissues under conjunctiva and on the cornea were excised. Then, 0.04% mitomycin C was applied at the subconjunctival space for 3 minutes using pieces of surgical sponge and the area was washed with 300 mL of saline. Next, we put cultivated epithelial sheet which was secured on the corneoscleral surface using 10 − 0 nylon sutures. A medical use contact lens (AirOptix, Alcon, Fort Worth, USA) was placed on the cornea at the end of the surgery. After surgery, 0.5% moxifloxacin (Vegamox, Alcon, Fort Worth, TX, USA) and 0.1% preservative-free betamethasone (Betamethasone PF, Nitten, Aichi, Japan) was initially applied four times a day at least for 1 month and gradually tapered. Three-dimensional analysis of corneal reflectivity using AS-OCT We evaluated the corneal reflectivity using CASIA2 ® (CASIA2, Tomey, Japan), before and 1, 3, 6, 12 months after COMET. To objectively quantify the severity of corneal opacity, the eyes of all participants were examined using AS-OCT. According to the previous report 6 , thirty-two rotating AS-OCT scans were obtained to reconstruct a three-dimensional model of the entire corneal configuration. Examination-quality data were assessed using a built-in program and results with serious errors were excluded. The corneal AS-OCT reflectivity, Xij , was quantified as grayscale units, ranging from 0 (darkest) to 255 (brightest) in each pixel of the AS-OCT images as 256 × 32 points in polar coordinates (1 ≤ i ≤ 256, 1 ≤ j ≤ 32) for an area of 10.2 mm. Then, Nij , the sum of Xij in three-dimensional space within a diameter of 3 and 6 mm, was calculated as follows. $$\:Nij=\frac{{\sum\:}_{k=0}^{n}Xij,k}{n}$$ $$\:Dsum=\frac{\sum\:Nij\bullet\:Wij}{W}$$ We measured epithelial thickness at each timepoint of each case, and calculated the following reflectivity parameters; individual thickness from the epithelial surface of the cornea as D(epi), 20 µm thickness from the endothelial surface of the cornea as D(endo), and residual stromal area as D(stroma). We evaluated D(epi), D(stroma), and D(endo) for two different areas: 3 and 6 mm in diameter. The data of 5 eyes with failed grafts were excluded from the failed timepoints. Statistical analysis The data were analyzed using GraphPad Prism (GraphPad Software, San Diego, CA, USA). D’Agostino and Pearson omnibus normality tests were used to assess whether the data showed a normal distribution. The data were presented as mean ± standard deviation for normally distributed variables. Nonparametric statistical methods were used for the values with skewed distributions. The Mann-Whitney U and Wilcoxon signed-rank tests were used to compare two non-normally distributed groups, and two non-normally distributed and dependent variables, respectively. To compare three or more non-normally distributed groups, the Kruskal-Wallis test was used, while the Dunn test was used to verify multiple comparisons. Spearman correlation analysis was used to assess the correlation among visual acuity, corneal reflectivity indices and corneal HOAs. A p-value < 0.05 was considered statistically significant. Results Clinical outcomes The demographic and corneal characteristics of the patients are shown in Table 1 . Cases 1. 2. 3. 10 showed lack of corneal epithelial phenotypic transformation at 2 months, and case 6 showed lack of phenotypic transformation at 12months. Kaplan-Meier survival analysis of Ocural ® are shown Fig. 1 . Failure was defined as recurrence of conjunctivalization more than LSCD grade 2B, persistent epithelial defects (defects involving more than half of corneal surface for more than 1 month), severe corneal opacification (complete obscuration of iris and pupil details), or failure to improve visual acuity 7 . Table 1 Patient demographics Case Age Sex Eye Disease Pre-op BCVA (logMAR) Pre-op Grade Post-op BCVA (logMAR) Post-op Grade Outcome at 1 year 1 56 F L Aniridia 2.7 3 2 3 Fail 2 79 F R SJS 2.7 3 1.5 3 Fail 3 63 F R SJS 1 3 1.4 3 Fail 4 64 F L Idiopathic 1.7 3 0.52 2A Success 5 58 M R Aniridia 1.4 3 1.1 1B Success 6 76 M L Idiopathic 2.7 3 1.3 3 Fail 7 36 F R Aniridia 2 3 1.2 1A Success 7 36 F L Aniridia 1.7 3 1.1 1B Success 8 84 F L OCP 2 3 0.3 1A Success 9 65 M L Aniridia 1.4 3 0.7 1A Success 10 45 F L SJS 2.7 3 2 3 Fail 11 16 F R GVHD 1.7 3 0.52 1C Success 11 16 F L GVHD 1.7 3 0.52 1B Success 12 50 M R Idiopathic 2.7 3 1.7 1B Success Corneal reflectivity before and after cultivated epithelial transplantation Corneal reflectivity results of different regions of each corneal layer are shown in Table 2 . Dunn's multiple comparisons test showed significant improvements of visual acuities of 1-, 3-, 6- and 12-months after surgery compared to preoperative values (p < 0.05), although there were little changes in corneal reflectivity between before and after surgery (Table 2 ). Table 2 Corneal reflectivity of each layer following cultivated epithelial transplantation Reflectivity Pre Post 1m Post 3m Post 6m Post 12m p (1m) p (3m) p (6m) p (12m) epi 3mm 167.9 ± 10.7 142.4 ± 39.3 162.1 ± 14.1 150.1 ± 29.6 158.6 ± 26.4 0.048 0.45 0.25 0.54 stroma 3mm 142.1 ± 14.6 140.1 ± 18.0 131.9 ± 11.9 132.6 ± 14.0 132.6 ± 16.4 0.54 0.76 0.09 0.14 endo 3mm 124.1 ± 17.5 125.9 ± 21.8 123.4 ± 15.3 121.0 ± 17.0 120.7 ± 8.3 0.88 0.47 0.37 0.89 epi 6mm 159.6 ± 10.0 134.5 ± 38.4 154.6 ± 11.2 142.6 ± 28.7 147.0 ± 30.2 0.02 0.44 0.24 0.46 stroma 6mm 123.7 ± 13.8 124.0 ± 16.4 116.7 ± 13.8 115.1 ± 12.7 115.0 ± 16.2 0.82 0.24 0.15 0.38 endo 6mm 103.2 ± 15.2 108.0 ± 18.6 106.7 ± 14.1 103.5 ± 15.1 99.5 ± 9.2 0.4 0.14 0.39 0.49 HOAs 3mm 3.09 ± 3.22 2.72 ± 2.38 2.46 ± 2.54 1.59 ± 1.24 1.25 ± 0.22 0.5 0.81 0.18 < 0.001 HOAs 6mm 10.88 ± 11.78 15.21 ± 15.54 8.30 ± 10.62 5.90 ± 6.42 4.57 ± 1.53 0.49 0.81 0.094 < 0.001 logMAR 2.01 ± 0.59 1.35 ± 0.65 1.21 ± 0.68 0.98 ± 0.48 1.03 ± 0.72 0.004 0.01 < 0.001 < 0.001 According to Spearman’s correlation test, significant positive correlations were observed between logMAR and stromal reflectivity at both 3 mm (Table 3 , ρ = 0.34, p = 0.012) and 6 mm (ρ = 0.47, p = 0.0003), indicating that increased stromal opacity was associated with worse visual acuity. Endothelial reflectivity at 3 mm also showed a weak but significant correlation (ρ = 0.27, p = 0.048). In contrast, epithelial reflectivity at both 3 mm and 6 mm showed no significant correlation with visual acuity. HOAs at 3 mm and 6 mm were also significantly correlated with logMAR (HOAs 3 mm: ρ = 0.39, p = 0.0033; HOAs 6 mm: ρ = 0.32, p = 0.017), suggesting that optical irregularities contribute to postoperative visual performance. Table 3 Spearman Correlation Analysis between visual acuities and other parameters Parameter Spearman ρ P-value Epi 3 mm 0.073 0.60 Stroma 3 mm 0.34 0.012 Endo 3 mm 0.27 0.048 Epi 6 mm 0.15 0.26 Stroma 6 mm 0.47 0.00030 Endo 6 mm 0.21 0.14 HOAs 3 mm 0.39 0.0033 HOAs 6 mm 0.32 0.017 A linear mixed-effects model was used to explore the association between corneal structural parameters and visual acuity. Using 3-mm zone data, both epithelial (β = 0.006, p = 0.011) and stromal (β = 0.028, p = 0.008) reflectivity were significantly associated with worse visual acuity. HOAs at 3 mm showed a marginal association with visual acuity (β = 0.059, p = 0.066), while endothelial reflectivity did not show a significant association. A similar model using 6-mm zone data revealed that epithelial (β = 0.008, p = 0.001) and stromal (β = 0.033, p = 0.002) reflectivity also significantly correlated with visual acuity. Endothelial reflectivity showed a trend with visual acuity (β = -0.019, p = 0.074), but HOAs at 6 mm did not show a significant correlation (β = 0.008, p = 0.25). Discussion Limbal epithelial stem cells are located in the limbus and play a pivotal role in keeping a transparent corneal epithelium, providing renewal and regenerated epithelial cells under normal condition and during wound healing. Total loss of stem cells leads to total LSCD, causing pain and severe vision impairment by the invading vascularized conjunctiva and keratinization. Treatment of total LSCD includes AULT, KLAL, CLET and COMET. However, in eyes with total LSCD, preoperative evaluation of stromal opacity remains challenging. Clinicians are often disappointed with unexpected opacification of the stroma after removing vascularized conjunctiva during surgeries (Fig. 2 ). Thus, a non-invasive and accurate method for preoperatively assessing corneal stromal opacity is highly desirable. The Pentacam ® has been widely used to quantify the corneal opacities in various corneal diseases, such as keratoconus 5 , Fuchs endothelial corneal dystrophy 8 , granular corneal dystrophy 9 – 11 , and post-keratoplasties 12 . The Pentacam Ⓡ has advantage in the diameter- and depth-specific quantification of corneal opacities. Furthermore, Pentacam Ⓡ densitometry values have been reported to be significantly correlated with poor visual acuity in abnormal conditions 13 – 14 . However, in eyes with dense corneal opacities, its short wavelength (400 nm) leads to signal saturation. The CASIA2 Ⓡ system using a 1310nm wavelength light, has an advantage in imaging the anterior segment structures in the eyes with severe corneal opacity 15 – 17 . Recently, a three-dimensional reflectivity assessment tool was developed for CASIA2 Ⓡ , which was used to evaluated guttae in FECD and SJS 18 – 19 . However, in the current study, we could not find any differences in long term reflectivity of epithelial, stromal, endothelial layers in LSCD before and after cultivated epithelial transplantation, although the clinical severity of LSCD and visual acuity significantly improved. It can be attributable to several reasons: First of all, it is possible to explain that densely opacified fibrovascular tissues could have affected the corneal reflectivity of the underlying stromal tissue as “acoustic shadow” in the ultrasound echo imaging (Fig. 3 ). Secondly, corneal epithelial destabilization in the early post COMET and delayed stabilization of the corneal epithelium with phenotypic transformation might have contributed to our current observations. Of note is that corneal HOAs and reflectivity of the epithelium significantly correlated with visual acuity of the patients. As in our previous studies on various corneal diseases, increased corneal HOAs were significantly associated with poor visual acuity. This study included 5 eyes of 4 aniridia patients with amblyopia due to macular hypoplasia, which can be a confounding factor. Interestingly, corneal HOAs were large in aniridia patients, as the corneal scarring extended into the stroma. Additionally, during the surgery, although fibrovascular tissues are usually clearly separated from the stroma in SJS, OCP and GVHD, the boarders of the epithelium and the stroma were obscure in aniridia patients, which might have induced larger corneal HOAs in aniridia, compared to the other etiologies in this study. In conclusion, corneal reflectivity and HOAs monitored with the AS-OCT reflectivity module was used to examine the amount of corneal backscattered light and optical quality before as well as 1-, 3-, 6-, and 12-months after Ocural ® . Cultivated epithelial transplantation produces significant early reductions in epithelial opacities associated with significant visual improvements. HOAs appear to improve after these changes owing to gradual stabilization and sustained integrity of the corneal epithelium. Declarations Data Availability The datasets used and analysed during the current study are available from the corresponding author on reasonable request. Funding Declaration This study is supported by the Grant-in-Aid for Scientific Research 23H03063 from the Ministry of Education, Culture, Sports, Science and Technology of Japan (T.Y.). The funding organization had no role in the design or conduct of this research. All authors certify that they have no involvement with any entity or organization with any financial interest in the subject matter or materials discussed in the manuscript. No financial disclosures. Author contribution Concept and design: R.O., and T. Y. Acquisition of clinical data: Y.M.O., M.S., T.S., H.K., O.M.A., Y.Y.Y., D.T., M.D., and T. Y. Critical revision of the manuscript for important intellectual content: M.D., and H.N. Management of this project: T.Y. Administrative, technical, or material support: T. Y. References Deng, S. X. et al. The International Limbal Stem Cell Deficiency Working Group Global Consensus on Definition, Classification, Diagnosis, and Staging of Limbal Stem Cell Deficiency. Cornea 38 , 364–375 (2019). Le, Q., Chauhan, T., Yung, M., Tseng, C. H. & Deng, S. X. Outcomes of Limbal Stem Cell Transplant: A Meta-analysis. JAMA Ophthalmol. 138 (6), 660–670 (2020). Pellegrini, G. et al. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet 349 (9057), 990–993 (1997). BALLEN PH. Mucous membrane grafts in chemical (lye) burns. Am. J. Ophthalmol. 55 , 302–312 (1963). Deng, S. X. et al. Global Consensus on Definition, Classification, Diagnosis, and Staging of Limbal Stem Cell Deficiency. Cornea 38 , 364–375 (2019). Suzuki, T. et al. Three-Dimensional Assessment of Descemet Membrane Reflectivity by Optical Coherence Tomography in Fuchs Endothelial Corneal Dystrophy. Cornea 43 , 207–213 (2024). Shimazaki, J. et al. Long-term outcomes of cultivated cell sheet transplantation for treating total limbal stem cell deficiency. Ocul Surf. 18 , 663–671 (2020). Lopes, B., Ramos, I. & Ambrósio, R. 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Recipient corneal thickness and visual outcome after Descemet's stripping automated endothelial keratoplasty. Br. J. Ophthalmol. 98 , 30–34 (2014). Pan, A. P. et al. Correlation among lens opacities classification system III grading, visual function index-14, pentacam nucleus staging, and objective scatter index for cataract assessment. Am. J. Ophthalmol. 159 , 241–247 (2015). Konstantopoulos, A., Kuo, J., Anderson, D. & Hossain, P. Assessment of the use of anterior segment optical coherence tomography in microbial keratitis. Am. J. Ophthalmol. 146 , 534–542 (2008). Takezawa, Y., Suzuki, T. & Shiraishi, A. Observation of Retrocorneal Plaques in Patients With Infectious Keratitis Using Anterior Segment Optical Coherence Tomography. Cornea 36 , 1237–1242 (2017). Daniel, M. C. et al. Childhood Lensectomy Is Associated with Static and Dynamic Reduction in Schlemm Canal Size: A Biomechanical Hypothesis of Glaucoma after Lensectomy. Ophthalmology 126 , 233–241 (2019). Suzuki, T. et al. Three-Dimensional Assessment of Descemet Membrane Reflectivity by Optical Coherence Tomography in Fuchs Endothelial Corneal Dystrophy. Cornea 43 , 207–213 (2024). Maeno, S. et al. Comparison of Scheimpflug and Anterior Segment Optical Coherence Tomography Imaging Parameters for Japanese Patients With Fuchs Endothelial Corneal Dystrophy With and Without TCF4 Repeat Expansions. Cornea 43 , 805–811 (2024). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 03 Sep, 2025 Reviews received at journal 02 Sep, 2025 Reviewers agreed at journal 29 Aug, 2025 Reviewers invited by journal 29 Aug, 2025 Editor assigned by journal 29 Aug, 2025 Editor invited by journal 29 Aug, 2025 Submission checks completed at journal 27 Aug, 2025 First submitted to journal 27 Aug, 2025 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-7406641","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":509838207,"identity":"e20dcf51-8738-4a6c-abdc-bb98bb3afbd0","order_by":0,"name":"Rintaro Ogino","email":"","orcid":"","institution":"Tokyo Dental College Ichikawa General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Rintaro","middleName":"","lastName":"Ogino","suffix":""},{"id":509838208,"identity":"27ceca07-5db7-46d8-8aab-ff4ea732b05e","order_by":1,"name":"Yurina Mori-Ogiwara","email":"","orcid":"","institution":"Tokyo Dental College Ichikawa General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yurina","middleName":"","lastName":"Mori-Ogiwara","suffix":""},{"id":509838214,"identity":"b7ba3da6-8c7d-47c1-8e26-8bec2ec8b4d8","order_by":2,"name":"Taiyo Shijo","email":"","orcid":"","institution":"Tokyo Dental College Ichikawa General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Taiyo","middleName":"","lastName":"Shijo","suffix":""},{"id":509838216,"identity":"51a6df37-e3f0-456b-a278-527d821fd3b7","order_by":3,"name":"Hirotsugu Kasamatu","email":"","orcid":"","institution":"Tokyo Dental College Ichikawa General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Hirotsugu","middleName":"","lastName":"Kasamatu","suffix":""},{"id":509838218,"identity":"85659e3a-4777-4a6d-a0d1-86d9c192281e","order_by":4,"name":"Osama Ibrahim","email":"","orcid":"","institution":"Tokyo Dental College Ichikawa General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Osama","middleName":"","lastName":"Ibrahim","suffix":""},{"id":509838219,"identity":"f642967b-b9d7-40db-add0-981aedb3a006","order_by":5,"name":"Mariko Shirane","email":"","orcid":"","institution":"Tokyo Dental College Ichikawa General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Mariko","middleName":"","lastName":"Shirane","suffix":""},{"id":509838222,"identity":"769a603a-c1ff-449b-8eed-c2b75a318b8a","order_by":6,"name":"Yukari Yagi-Yaguchi","email":"","orcid":"","institution":"Tokyo Dental College Ichikawa General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Yukari","middleName":"","lastName":"Yagi-Yaguchi","suffix":""},{"id":509838223,"identity":"baee1c80-d3a3-4340-a40c-1f3a339b2ee1","order_by":7,"name":"Daisuke Tomida","email":"","orcid":"","institution":"Tokyo Dental College Ichikawa General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Daisuke","middleName":"","lastName":"Tomida","suffix":""},{"id":509838224,"identity":"2c3fbe03-ea8d-48d7-95b3-03aad097c73b","order_by":8,"name":"Hisashi Noma","email":"","orcid":"","institution":"The Institute of Statistical Mathematics","correspondingAuthor":false,"prefix":"","firstName":"Hisashi","middleName":"","lastName":"Noma","suffix":""},{"id":509838225,"identity":"b3d73071-c151-4b63-b3b2-6397d898a1a6","order_by":9,"name":"Murat Dogru","email":"","orcid":"","institution":"Tokyo Dental College Ichikawa General Hospital","correspondingAuthor":false,"prefix":"","firstName":"Murat","middleName":"","lastName":"Dogru","suffix":""},{"id":509838226,"identity":"977da19f-1bfe-4a76-a821-dc33c6d86f0a","order_by":10,"name":"Takefumi Yamaguchi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5ElEQVRIiWNgGAWjYBCDBDYG5gMMPFAOkVrY2BIbSNPCwMZjCNOCHxgcP5348WubXR6ffM/3B29qGOT5GxiePcCr5UzuZmnZtuRiNjbejY1zjjEYzjjAkG6AV8uB3A3Skm0HEtuAWpp5GxgYNzAwpEng1XL+7ebfEC08D0Fa7AlruZG7TfIjRAsjSEsiQS2SN95us2Y4lwzUkmY4c84xieQZhwn4he987uabP8rsEuc3H37w4U2NjW1/e0/aA3xaFA4wMDAjRYcEiJuGTweDfAMDA+MPVDH2Y3i1jIJRMApGwYgDAEauTKvnfVygAAAAAElFTkSuQmCC","orcid":"","institution":"Tokyo Dental College Ichikawa General Hospital","correspondingAuthor":true,"prefix":"","firstName":"Takefumi","middleName":"","lastName":"Yamaguchi","suffix":""}],"badges":[],"createdAt":"2025-08-19 09:08:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7406641/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7406641/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90881053,"identity":"e187e037-e20a-4b74-ae9b-9dcbb6de45f1","added_by":"auto","created_at":"2025-09-09 09:39:39","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":73593,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan-Meier survival analysis of Ocural\u003csup\u003eⓇ\u003c/sup\u003e. The Kaplan-Meier estimated a 66% graft survival rate at 12 months, with most failures occurring within the first 2 months.\u003c/p\u003e","description":"","filename":"figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-7406641/v1/80823ea267a41169281890ae.png"},{"id":90881059,"identity":"119d1290-5c6a-4895-83e1-71137f35f66e","added_by":"auto","created_at":"2025-09-09 09:39:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1063523,"visible":true,"origin":"","legend":"\u003cp\u003eCorneal opacities before and after removing vascularized conjunctiva during surgeries. After removing vascularized conjunctiva, there were unexpected corneal stromal opacities.\u003c/p\u003e","description":"","filename":"figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-7406641/v1/5dd84faaf4600b42c24ff7c7.png"},{"id":90881058,"identity":"3aa995d2-138d-4b1b-b72a-20aa37628a30","added_by":"auto","created_at":"2025-09-09 09:39:39","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":221402,"visible":true,"origin":"","legend":"\u003cp\u003eAS-OCT image of Case 2 before the surgery. This shows an “acoustic shadow” in the corneal stromal region beneath the thickened epithelium. It can lead to underestimate reflectivity of the corneal stroma.\u003c/p\u003e","description":"","filename":"figure3.png","url":"https://assets-eu.researchsquare.com/files/rs-7406641/v1/0ac2574192406534b1e81b45.png"},{"id":90885180,"identity":"6a637548-a362-4b95-a659-ebdfd34c3069","added_by":"auto","created_at":"2025-09-09 10:03:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2847655,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7406641/v1/e8dbda41-77b4-4473-b312-cf9a4bcfbb6d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Three-Dimensional Reflectivity Analysis of Corneal Layers Following Cultivated Epithelial Transplantation using Optical Coherence Tomography Short title: Corneal reflectivity analysis following cultivated epithelial transplantation","fulltext":[{"header":"Introduction","content":"\u003cp\u003eLimbal stem cell deficiency (LSCD) is a severe ocular surface disorder caused by complete loss of limbal stem cells. These cells are essential for maintaining the integrity of the corneal epithelium and for preserving the barrier function of the limbus\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Their loss results in conjunctival ingrowth over the corneal surface, leading to marked opacification and substantial visual impairment. Currently available therapeutic strategies include autologous limbal transplantation (AULT) and keratolimbal allograft (KLAL). While AULT avoids systemic immunosuppression and carries a relatively low risk of graft rejection, it is only feasible in unilateral cases. In contrast, KLAL can be applied to bilateral disease but is limited by its high risk of rejection and the requirement for long-term immunosuppressive therapy\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn 1997, Pellegrini et al. reported a novel procedure utilizing \u003cem\u003eex vivo\u003c/em\u003e cultivated autologous limbal epithelial cells for ocular surface reconstruction\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. In this technique, epithelial cells taken from the limbus of the healthy eye are cultured to generate cohesive sheets of authentic corneal epithelium for transplantation. More recently, Nepic\u0026reg;, an autologous cultured corneal epithelial product, was launched in March 2020 for the management of unilateral LSCD. Nevertheless, LSCD frequently develops bilaterally. Its underlying causes include genetic (e.g., aniridia), acquired (e.g., ocular cicatricial pemphigoid [OCP], Stevens\u0026ndash;Johnson syndrome [SJS], trauma, or chemical burns), or idiopathic. In such cases, healthy donor limbal tissue is usually absent or insufficient for autologous transplantation.\u003c/p\u003e\u003cp\u003eOral mucosal epithelial cells has emerged as a promising alternative source because it shares structural and functional similarities with corneal epithelium\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. In June 2021, the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan approved Ocural\u003csup\u003e\u0026reg;\u003c/sup\u003e, the first \u003cem\u003eex vivo\u003c/em\u003e cultivated oral mucosal epithelial transplantation (COMET) product for the treatment of bilateral LSCD.\u003c/p\u003e\u003cp\u003eMaintaining corneal transparency is crucial for visual function, yet stromal opacity in LSCD is difficult to assess accurately, particularly when epithelial opacification is severe, using slit-lamp examination alone. Anterior segment optical coherence tomography (AS-OCT), which employs 1310-nm infrared light, enables non-invasive, reproducible, and objective quantification of corneal reflectivity, even in markedly opaque corneas. The aim of the present study was to analyze temporal changes in corneal reflectivity following COMET with Ocural\u003csup\u003e\u0026reg;\u003c/sup\u003e and to determine how these changes are associated with stromal opacity and postoperative visual outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe study followed the principles of the Declaration of Helsinki and was approved by Institutional Review Board of Tokyo Dental College Ichikawa General Hospital (Approval number: I23-54, Approval date: October 13th, 2021). Patient data were anonymized prior to access and/or analysis. Informed consent has been obtained from all patients and/or legal guardians. In this prospective study, 14 eyes of 12 patients with LSCD undergoing cultivated epithelial transplantation at Tokyo Dental College Ichikawa General Hospital from April 2022 to June 2024 were included for analysis. LSCD was diagnosed, based on the international expert consensus on LSCD criteria\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. In this study, all patients with Grade 3 LSCD underwent cultivated oral mucosal epithelial transplantation using Ocural\u003csup\u003e\u0026reg;\u003c/sup\u003e(JTEC, Aichi, Japan).\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eSurgical methods\u003c/h2\u003e\u003cp\u003eCOMET surgeries were performed by one of the two experienced surgeons (T.Y. and D.T.). Briefly, an oral mucosal biopsy specimen from buccal mucosa (5 mm \u0026times; 20 mm) was obtained from the subjects, and sent to JTEC laboratory to produce cultivated epithelial sheet. After 4-weeks of culture, sheets were sent back to Tokyo Dental College Ichikawa General Hospital and used for epithelial transplantation. After 360˚conjunctival peritomy, fibrovascular tissues under conjunctiva and on the cornea were excised. Then, 0.04% mitomycin C was applied at the subconjunctival space for 3 minutes using pieces of surgical sponge and the area was washed with 300 mL of saline. Next, we put cultivated epithelial sheet which was secured on the corneoscleral surface using 10\u0026thinsp;\u0026minus;\u0026thinsp;0 nylon sutures. A medical use contact lens (AirOptix, Alcon, Fort Worth, USA) was placed on the cornea at the end of the surgery. After surgery, 0.5% moxifloxacin (Vegamox, Alcon, Fort Worth, TX, USA) and 0.1% preservative-free betamethasone (Betamethasone PF, Nitten, Aichi, Japan) was initially applied four times a day at least for 1 month and gradually tapered.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eThree-dimensional analysis of corneal reflectivity using AS-OCT\u003c/h3\u003e\n\u003cp\u003eWe evaluated the corneal reflectivity using CASIA2\u003csup\u003e\u0026reg;\u003c/sup\u003e (CASIA2, Tomey, Japan), before and 1, 3, 6, 12 months after COMET. To objectively quantify the severity of corneal opacity, the eyes of all participants were examined using AS-OCT. According to the previous report\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e, thirty-two rotating AS-OCT scans were obtained to reconstruct a three-dimensional model of the entire corneal configuration. Examination-quality data were assessed using a built-in program and results with serious errors were excluded. The corneal AS-OCT reflectivity, \u003cem\u003eXij\u003c/em\u003e, was quantified as grayscale units, ranging from 0 (darkest) to 255 (brightest) in each pixel of the AS-OCT images as 256 \u0026times; 32 points in polar coordinates (1\u0026thinsp;\u0026le;\u0026thinsp;\u003cem\u003ei\u003c/em\u003e \u0026le;\u0026thinsp;256, 1\u0026thinsp;\u0026le;\u0026thinsp;\u003cem\u003ej\u003c/em\u003e \u0026le;\u0026thinsp;32) for an area of 10.2 mm. Then, \u003cem\u003eNij\u003c/em\u003e, the sum of \u003cem\u003eXij\u003c/em\u003e in three-dimensional space within a diameter of 3 and 6 mm, was calculated as follows.\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\:Nij=\\frac{{\\sum\\:}_{k=0}^{n}Xij,k}{n}$$\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Equb\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equb\" name=\"EquationSource\"\u003e\n$$\\:Dsum=\\frac{\\sum\\:Nij\\bullet\\:Wij}{W}$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eWe measured epithelial thickness at each timepoint of each case, and calculated the following reflectivity parameters; individual thickness from the epithelial surface of the cornea as D(epi), 20 \u0026micro;m thickness from the endothelial surface of the cornea as D(endo), and residual stromal area as D(stroma). We evaluated D(epi), D(stroma), and D(endo) for two different areas: 3 and 6 mm in diameter. The data of 5 eyes with failed grafts were excluded from the failed timepoints.\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eThe data were analyzed using GraphPad Prism (GraphPad Software, San Diego, CA, USA). D\u0026rsquo;Agostino and Pearson omnibus normality tests were used to assess whether the data showed a normal distribution. The data were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation for normally distributed variables. Nonparametric statistical methods were used for the values with skewed distributions. The Mann-Whitney U and Wilcoxon signed-rank tests were used to compare two non-normally distributed groups, and two non-normally distributed and dependent variables, respectively. To compare three or more non-normally distributed groups, the Kruskal-Wallis test was used, while the Dunn test was used to verify multiple comparisons. Spearman correlation analysis was used to assess the correlation among visual acuity, corneal reflectivity indices and corneal HOAs. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eClinical outcomes\u003c/h2\u003e\u003cp\u003eThe demographic and corneal characteristics of the patients are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Cases 1. 2. 3. 10 showed lack of corneal epithelial phenotypic transformation at 2 months, and case 6 showed lack of phenotypic transformation at 12months. Kaplan-Meier survival analysis of Ocural\u003csup\u003e\u0026reg;\u003c/sup\u003e are shown Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Failure was defined as recurrence of conjunctivalization more than LSCD grade 2B, persistent epithelial defects (defects involving more than half of corneal surface for more than 1 month), severe corneal opacification (complete obscuration of iris and pupil details), or failure to improve visual acuity\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient demographics\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" 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colname=\"c2\"\u003e\u003cp\u003e58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAniridia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSuccess\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIdiopathic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eFail\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAniridia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSuccess\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAniridia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSuccess\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e84\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eOCP\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSuccess\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eAniridia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSuccess\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eSJS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eFail\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGVHD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSuccess\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e11\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eF\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eL\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGVHD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.52\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSuccess\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e50\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eM\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eIdiopathic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eSuccess\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eCorneal reflectivity before and after cultivated epithelial transplantation\u003c/h2\u003e\u003cp\u003eCorneal reflectivity results of different regions of each corneal layer are shown in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. Dunn's multiple comparisons test showed significant improvements of visual acuities of 1-, 3-, 6- and 12-months after surgery compared to preoperative values (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05), although there were little changes in corneal reflectivity between before and after surgery (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eCorneal reflectivity of each layer following cultivated epithelial transplantation\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eReflectivity\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePre\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePost 1m\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePost 3m\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003ePost 6m\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePost 12m\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003ep (1m)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003ep (3m)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003ep (6m)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003ep (12m)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eepi 3mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e167.9\u0026thinsp;\u0026plusmn;\u0026thinsp;10.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e142.4\u0026thinsp;\u0026plusmn;\u0026thinsp;39.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e162.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e150.1\u0026thinsp;\u0026plusmn;\u0026thinsp;29.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e158.6\u0026thinsp;\u0026plusmn;\u0026thinsp;26.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.048\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.45\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.25\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.54\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003estroma 3mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e142.1\u0026thinsp;\u0026plusmn;\u0026thinsp;14.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e140.1\u0026thinsp;\u0026plusmn;\u0026thinsp;18.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e131.9\u0026thinsp;\u0026plusmn;\u0026thinsp;11.9\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e132.6\u0026thinsp;\u0026plusmn;\u0026thinsp;14.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e132.6\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.76\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eendo 3mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e124.1\u0026thinsp;\u0026plusmn;\u0026thinsp;17.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e125.9\u0026thinsp;\u0026plusmn;\u0026thinsp;21.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e123.4\u0026thinsp;\u0026plusmn;\u0026thinsp;15.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e121.0\u0026thinsp;\u0026plusmn;\u0026thinsp;17.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e120.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.88\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.37\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.89\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eepi 6mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e159.6\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e134.5\u0026thinsp;\u0026plusmn;\u0026thinsp;38.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e154.6\u0026thinsp;\u0026plusmn;\u0026thinsp;11.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e142.6\u0026thinsp;\u0026plusmn;\u0026thinsp;28.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e147.0\u0026thinsp;\u0026plusmn;\u0026thinsp;30.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.44\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.46\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003estroma 6mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e123.7\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e124.0\u0026thinsp;\u0026plusmn;\u0026thinsp;16.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e116.7\u0026thinsp;\u0026plusmn;\u0026thinsp;13.8\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e115.1\u0026thinsp;\u0026plusmn;\u0026thinsp;12.7\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e115.0\u0026thinsp;\u0026plusmn;\u0026thinsp;16.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.82\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.38\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eendo 6mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e103.2\u0026thinsp;\u0026plusmn;\u0026thinsp;15.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e108.0\u0026thinsp;\u0026plusmn;\u0026thinsp;18.6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e106.7\u0026thinsp;\u0026plusmn;\u0026thinsp;14.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e103.5\u0026thinsp;\u0026plusmn;\u0026thinsp;15.1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e99.5\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.4\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e0.49\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHOAs 3mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e3.09\u0026thinsp;\u0026plusmn;\u0026thinsp;3.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e2.72\u0026thinsp;\u0026plusmn;\u0026thinsp;2.38\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e2.46\u0026thinsp;\u0026plusmn;\u0026thinsp;2.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e1.59\u0026thinsp;\u0026plusmn;\u0026thinsp;1.24\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e1.25\u0026thinsp;\u0026plusmn;\u0026thinsp;0.22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.5\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.18\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHOAs 6mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e10.88\u0026thinsp;\u0026plusmn;\u0026thinsp;11.78\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e15.21\u0026thinsp;\u0026plusmn;\u0026thinsp;15.54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e8.30\u0026thinsp;\u0026plusmn;\u0026thinsp;10.62\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e5.90\u0026thinsp;\u0026plusmn;\u0026thinsp;6.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e4.57\u0026thinsp;\u0026plusmn;\u0026thinsp;1.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.81\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e0.094\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003elogMAR\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e\u003cp\u003e2.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.59\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e\u003cp\u003e1.35\u0026thinsp;\u0026plusmn;\u0026thinsp;0.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c4\"\u003e\u003cp\u003e1.21\u0026thinsp;\u0026plusmn;\u0026thinsp;0.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c5\"\u003e\u003cp\u003e0.98\u0026thinsp;\u0026plusmn;\u0026thinsp;0.48\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c6\"\u003e\u003cp\u003e1.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.72\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c10\"\u003e\u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAccording to Spearman\u0026rsquo;s correlation test, significant positive correlations were observed between logMAR and stromal reflectivity at both 3 mm (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, ρ\u0026thinsp;=\u0026thinsp;0.34, p\u0026thinsp;=\u0026thinsp;0.012) and 6 mm (ρ\u0026thinsp;=\u0026thinsp;0.47, p\u0026thinsp;=\u0026thinsp;0.0003), indicating that increased stromal opacity was associated with worse visual acuity. Endothelial reflectivity at 3 mm also showed a weak but significant correlation (ρ\u0026thinsp;=\u0026thinsp;0.27, p\u0026thinsp;=\u0026thinsp;0.048). In contrast, epithelial reflectivity at both 3 mm and 6 mm showed no significant correlation with visual acuity. HOAs at 3 mm and 6 mm were also significantly correlated with logMAR (HOAs 3 mm: ρ\u0026thinsp;=\u0026thinsp;0.39, p\u0026thinsp;=\u0026thinsp;0.0033; HOAs 6 mm: ρ\u0026thinsp;=\u0026thinsp;0.32, p\u0026thinsp;=\u0026thinsp;0.017), suggesting that optical irregularities contribute to postoperative visual performance.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSpearman Correlation Analysis between visual acuities and other parameters\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParameter\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eSpearman ρ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEpi 3 mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.073\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStroma 3 mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.34\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.012\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEndo 3 mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.27\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.048\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEpi 6 mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.26\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStroma 6 mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.47\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.00030\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEndo 6 mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.14\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHOAs 3 mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.39\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.0033\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHOAs 6 mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e0.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e0.017\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eA linear mixed-effects model was used to explore the association between corneal structural parameters and visual acuity. Using 3-mm zone data, both epithelial (β\u0026thinsp;=\u0026thinsp;0.006, p\u0026thinsp;=\u0026thinsp;0.011) and stromal (β\u0026thinsp;=\u0026thinsp;0.028, p\u0026thinsp;=\u0026thinsp;0.008) reflectivity were significantly associated with worse visual acuity. HOAs at 3 mm showed a marginal association with visual acuity (β\u0026thinsp;=\u0026thinsp;0.059, p\u0026thinsp;=\u0026thinsp;0.066), while endothelial reflectivity did not show a significant association. A similar model using 6-mm zone data revealed that epithelial (β\u0026thinsp;=\u0026thinsp;0.008, p\u0026thinsp;=\u0026thinsp;0.001) and stromal (β\u0026thinsp;=\u0026thinsp;0.033, p\u0026thinsp;=\u0026thinsp;0.002) reflectivity also significantly correlated with visual acuity. Endothelial reflectivity showed a trend with visual acuity (β = -0.019, p\u0026thinsp;=\u0026thinsp;0.074), but HOAs at 6 mm did not show a significant correlation (β\u0026thinsp;=\u0026thinsp;0.008, p\u0026thinsp;=\u0026thinsp;0.25).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eLimbal epithelial stem cells are located in the limbus and play a pivotal role in keeping a transparent corneal epithelium, providing renewal and regenerated epithelial cells under normal condition and during wound healing. Total loss of stem cells leads to total LSCD, causing pain and severe vision impairment by the invading vascularized conjunctiva and keratinization. Treatment of total LSCD includes AULT, KLAL, CLET and COMET. However, in eyes with total LSCD, preoperative evaluation of stromal opacity remains challenging. Clinicians are often disappointed with unexpected opacification of the stroma after removing vascularized conjunctiva during surgeries (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Thus, a non-invasive and accurate method for preoperatively assessing corneal stromal opacity is highly desirable.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eThe Pentacam\u003csup\u003e\u0026reg;\u003c/sup\u003e has been widely used to quantify the corneal opacities in various corneal diseases, such as keratoconus\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, Fuchs endothelial corneal dystrophy\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, granular corneal dystrophy\u003csup\u003e\u003cspan additionalcitationids=\"CR10\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e, and post-keratoplasties\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. The Pentacam\u003csup\u003eⓇ\u003c/sup\u003e has advantage in the diameter- and depth-specific quantification of corneal opacities. Furthermore, Pentacam\u003csup\u003eⓇ\u003c/sup\u003e densitometry values have been reported to be significantly correlated with poor visual acuity in abnormal conditions\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. However, in eyes with dense corneal opacities, its short wavelength (400 nm) leads to signal saturation. The CASIA2\u003csup\u003eⓇ\u003c/sup\u003e system using a 1310nm wavelength light, has an advantage in imaging the anterior segment structures in the eyes with severe corneal opacity\u003csup\u003e\u003cspan additionalcitationids=\"CR16\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Recently, a three-dimensional reflectivity assessment tool was developed for CASIA2\u003csup\u003eⓇ\u003c/sup\u003e, which was used to evaluated guttae in FECD and SJS\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. However, in the current study, we could not find any differences in long term reflectivity of epithelial, stromal, endothelial layers in LSCD before and after cultivated epithelial transplantation, although the clinical severity of LSCD and visual acuity significantly improved. It can be attributable to several reasons: First of all, it is possible to explain that densely opacified fibrovascular tissues could have affected the corneal reflectivity of the underlying stromal tissue as \u0026ldquo;acoustic shadow\u0026rdquo; in the ultrasound echo imaging (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Secondly, corneal epithelial destabilization in the early post COMET and delayed stabilization of the corneal epithelium with phenotypic transformation might have contributed to our current observations.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eOf note is that corneal HOAs and reflectivity of the epithelium significantly correlated with visual acuity of the patients. As in our previous studies on various corneal diseases, increased corneal HOAs were significantly associated with poor visual acuity. This study included 5 eyes of 4 aniridia patients with amblyopia due to macular hypoplasia, which can be a confounding factor. Interestingly, corneal HOAs were large in aniridia patients, as the corneal scarring extended into the stroma. Additionally, during the surgery, although fibrovascular tissues are usually clearly separated from the stroma in SJS, OCP and GVHD, the boarders of the epithelium and the stroma were obscure in aniridia patients, which might have induced larger corneal HOAs in aniridia, compared to the other etiologies in this study.\u003c/p\u003e\u003cp\u003eIn conclusion, corneal reflectivity and HOAs monitored with the AS-OCT reflectivity module was used to examine the amount of corneal backscattered light and optical quality before as well as 1-, 3-, 6-, and 12-months after Ocural\u003csup\u003e\u0026reg;\u003c/sup\u003e. Cultivated epithelial transplantation produces significant early reductions in epithelial opacities associated with significant visual improvements. HOAs appear to improve after these changes owing to gradual stabilization and sustained integrity of the corneal epithelium.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding Declaration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is supported by the Grant-in-Aid for Scientific Research 23H03063 from the Ministry of Education, Culture, Sports, Science and Technology of Japan (T.Y.). The funding organization had no role in the design or conduct of this research. All authors certify that they have no involvement with any entity or organization with any financial interest in the subject matter or materials discussed in the manuscript.\u003c/p\u003e\n\u003cp\u003eNo financial disclosures.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contribution\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConcept and design: R.O., and T. Y.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcquisition of clinical data: Y.M.O., M.S., T.S., H.K., O.M.A., Y.Y.Y., D.T., M.D., and T. Y.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCritical revision of the manuscript for important intellectual content: M.D., and H.N.\u003c/p\u003e\n\u003cp\u003eManagement of this project: T.Y.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdministrative, technical, or material support: T. Y.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDeng, S. X. et al. The International Limbal Stem Cell Deficiency Working Group Global Consensus on Definition, Classification, Diagnosis, and Staging of Limbal Stem Cell Deficiency. \u003cem\u003eCornea\u003c/em\u003e \u003cb\u003e38\u003c/b\u003e, 364\u0026ndash;375 (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\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 \u003cb\u003e138\u003c/b\u003e (6), 660\u0026ndash;670 (2020).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePellegrini, G. et al. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. \u003cem\u003eLancet\u003c/em\u003e \u003cb\u003e349\u003c/b\u003e (9057), 990\u0026ndash;993 (1997).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBALLEN PH. Mucous membrane grafts in chemical (lye) burns. \u003cem\u003eAm. J. 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Ophthalmol.\u003c/em\u003e \u003cb\u003e251\u003c/b\u003e, 2575\u0026ndash;2584 (2013).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eIvarsen, A. \u0026amp; Hjortdal, J. Recipient corneal thickness and visual outcome after Descemet's stripping automated endothelial keratoplasty. \u003cem\u003eBr. J. Ophthalmol.\u003c/em\u003e \u003cb\u003e98\u003c/b\u003e, 30\u0026ndash;34 (2014).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003ePan, A. P. et al. Correlation among lens opacities classification system III grading, visual function index-14, pentacam nucleus staging, and objective scatter index for cataract assessment. \u003cem\u003eAm. J. Ophthalmol.\u003c/em\u003e \u003cb\u003e159\u003c/b\u003e, 241\u0026ndash;247 (2015).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKonstantopoulos, A., Kuo, J., Anderson, D. \u0026amp; Hossain, P. Assessment of the use of anterior segment optical coherence tomography in microbial keratitis. \u003cem\u003eAm. J. Ophthalmol.\u003c/em\u003e \u003cb\u003e146\u003c/b\u003e, 534\u0026ndash;542 (2008).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTakezawa, Y., Suzuki, T. \u0026amp; Shiraishi, A. Observation of Retrocorneal Plaques in Patients With Infectious Keratitis Using Anterior Segment Optical Coherence Tomography. \u003cem\u003eCornea\u003c/em\u003e \u003cb\u003e36\u003c/b\u003e, 1237\u0026ndash;1242 (2017).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eDaniel, M. C. et al. Childhood Lensectomy Is Associated with Static and Dynamic Reduction in Schlemm Canal Size: A Biomechanical Hypothesis of Glaucoma after Lensectomy. \u003cem\u003eOphthalmology\u003c/em\u003e \u003cb\u003e126\u003c/b\u003e, 233\u0026ndash;241 (2019).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSuzuki, T. et al. Three-Dimensional Assessment of Descemet Membrane Reflectivity by Optical Coherence Tomography in Fuchs Endothelial Corneal Dystrophy. \u003cem\u003eCornea\u003c/em\u003e \u003cb\u003e43\u003c/b\u003e, 207\u0026ndash;213 (2024).\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eMaeno, S. et al. Comparison of Scheimpflug and Anterior Segment Optical Coherence Tomography Imaging Parameters for Japanese Patients With Fuchs Endothelial Corneal Dystrophy With and Without TCF4 Repeat Expansions. \u003cem\u003eCornea\u003c/em\u003e \u003cb\u003e43\u003c/b\u003e, 805\u0026ndash;811 (2024).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"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":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Limbal stem cell deficiency, stromal opacity, higher order aberration, anterior segment optical coherence tomography, cultivated epithelial transplantation","lastPublishedDoi":"10.21203/rs.3.rs-7406641/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7406641/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eLimbal stem cell deficiency (LSCD) is a debilitating condition that impairs corneal transparency and visual function due to damage of the limbal niche. Traditional treatments often fall short in bilateral cases or severe opacity. Cultivated oral mucosal epithelial transplantation (COMET) has recently emerged as a novel regenerative approach to restore the ocular surface in LSCD. Here we show that COMET leads to significant improvements in visual acuity and reduction of corneal surface irregularities. Using anterior segment optical coherence tomography (OCT), we evaluated corneal reflectivity in the epithelial, stromal, and endothelial layers over time. We found early reduction in epithelial opacity, while stromal reflectivity showed a persistent correlation with visual outcomes. Higher-order aberrations also decreased postoperatively and were significantly associated with better vision. These findings demonstrate the clinical potential of COMET to improve both structural and optical quality of the cornea and highlight the value of quantitative OCT imaging in evaluating therapeutic response. This study provides new insight into visual rehabilitation mechanisms in patients with severe LSCD and supports broader application of cultivated epithelial cell therapies in ocular surface reconstruction.\u003c/p\u003e","manuscriptTitle":"Three-Dimensional Reflectivity Analysis of Corneal Layers Following Cultivated Epithelial Transplantation using Optical Coherence Tomography Short title: Corneal reflectivity analysis following cultivated epithelial transplantation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-09 09:39:34","doi":"10.21203/rs.3.rs-7406641/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"28233460821190479999167465195279621769","date":"2025-09-03T17:25:19+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-02T18:30:04+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"262746429031982437184210750675536851002","date":"2025-08-29T19:46:45+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-29T14:23:27+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-29T14:07:42+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-08-29T07:04:03+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-27T23:21:51+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2025-08-27T23:19:23+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4b423d94-6cde-4fdb-a401-05724517c7fa","owner":[],"postedDate":"September 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":54153228,"name":"Health sciences/Diseases"},{"id":54153229,"name":"Health sciences/Medical research"}],"tags":[],"updatedAt":"2025-09-09T09:39:34+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-09 09:39:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7406641","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7406641","identity":"rs-7406641","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}