Comparison of inverted inner limiting membrane flap technique and traditional peeling for visual recovery and microscopic structural improvement in patients with macular holes: a meta-analysis

Comparison of inverted inner limiting membrane flap technique and traditional peeling for visual recovery and microscopic structural improvement in patients with macular holes: a meta-analysis | 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 Research Article Comparison of inverted inner limiting membrane flap technique and traditional peeling for visual recovery and microscopic structural improvement in patients with macular holes: a meta-analysis Qiang Tang, Huan Wan, Xuezhao Zhao, Zhumei Yang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7927324/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 9 You are reading this latest preprint version Abstract Background A meta-analysis comparing the efficacy of internal limiting membrane (ILM) peeling and inverted ILM flap techniques for the treatment of macular holes (MH). Methods Researchers searched the Cochrane Library and PubMed database for relevant randomized controlled trials published from the establishment of the database to June 30, 2025. The control and intervention groups were the ILM peeling group and the inverted ILM flap group, respectively. Literature quality assessment was conducted using the Cochrane Risk of Bias Assessment Tool. Meta-analysis was performed using Review Manager and Stata software. Anatomical closure rate and best-corrected visual acuity (BCVA) were used as primary outcomes. External limiting membrane (ELM) and ellipsoid zone (EZ) were used as secondary outcomes. Results A total of 202 relevant literature articles were screened, and 10 studies were ultimately included. Compared with the traditional ILM peeling group (ILM peeling), the closure rate was significantly higher in the inverted inner limiting membrane flap group (InFlap). In the ≥ 600 μm subgroup, the closure rate was significantly higher with InFlap. there was no statistically significant difference in closure rates between ILM peeling and InFlap in terms of mean BCVA. And also, ILM peeling was higher than InFlap in either the <600 μm subgroup or the ≥ 600 μm subgroup. the EZ was significantly higher in the ILM peeling compared to the InFlap. Conclusions For MHs with a diameter greater than 600 µm, the inverted ILM flap technique can significantly improve anatomical closure rates. Trial registration Registration number: CRD420251139305. This study was registered at PROSPERO and no modifications were made. internal limiting membrane peeling inverted internal limiting membrane flap techniques macular holes diameter ≥ 600 µm meta-analysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Macular hole (MH) is a retinal disease that poses a serious threat to vision. It generally refers to a defect in the neural retina at the center of the macular area. the formation of MH leads to symptoms such as decreased central vision, distorted vision, and central scotoma, causing a massive impairment of visual function, and is difficult and risky to treat (1). Currently, inner limiting membrane (ILM) peeling vitrectomy remains the gold standard for treating MH (2). A retrospective study found that for patients with larger hole diameters, the anatomical success rate of traditional ILM peeling drops to 60% (3). A well-known fact is that MH is classified into three categories based on diameter: small holes (≤ 250 µm), medium holes (> 250 µm, ≤ 400 µm), and large holes (> 400 µm). Michalewska et al. were the first to modify the standard MH surgery, improving visual function and anatomical outcomes in patients with > 400 µm holes. The modified surgery is called the inverted ILM flap technique (4). With the widespread application of the inverted ILM flap technique, the number of supporting literature has been increasing (5, 6). However, a notable issue remains: when using traditional ILM peeling techniques to treat MHs with a diameter > 400 µm, although the surgical success rate may not reach 100%, most tears can still be closed; the true risk of surgical failure may lie in certain larger-diameter MHs (e.g., exceeding 600 µm). For such large-diameter MHs, which is superior: traditional ILM peeling technique or modified ILM flap coverage technique? To date, there is still no authoritative conclusion on this matter. The primary outcomes assessed after MH surgery include anatomical closure and best-corrected visual acuity (BCVA). BCVA may be related to foveal microstructures (7). In recent years, optical coherence tomography (OCT) has been widely used for the diagnosis and prognosis of MH. OCT parameters, such as the external limiting membrane (ELM) and ellipsoid zone (EZ), have also been used to predict postoperative visual acuity (8, 9). However, there are relatively few meta-analyses focusing on postoperative OCT parameters in MH patients. In this study, we collected randomized controlled clinical trials (RCTs) comparing ILM peeling vs. inverted ILM flap techniques for the treatment of MH. Patients were divided into two subgroups based on the minimum MH diameter: ≤ 600 micrometers and > 600 micrometers. We assessed postoperative anatomical closure rates, BCVA, and OCT parameters, including the ELM and EZ. This study provides evidence-based medical evidence to address the question of which technique—ILM peeling or inverted ILM flap—is superior in MH surgery. Methods Literature retrieval According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, published studies about randomized controlled trials were retrieved from public databases including Cochrane Library and PubMed. The publication time started from the beginning of the establishment of the library to June 30, 2025, and the language of the searched articles was English. In addition, to avoid omitting any studies, we carefully searched the references of the included articles as a supplement. Included literature was screened according to the PRISMA 2020 protocol (PRISMA Checklist, Supplementary Table 1). First, following the PICOS (Population, Intervention, Comparison, Outcome, Study design) principle, two members conducted an initial screening of the articles using a combination of MeSH and free-text search terms (search strategy, Supplementary Table 2). If the two members disagreed on the inclusion of the same article, a senior third party made the final decision. Literature screening Inclusion criteria: (1) Population: MH patients; (2) Intervention: inverted ILM flap technique; (3) Control: traditional ILM peeling technique; (4) Primary outcomes: anatomical closure rate and BCVA; (5) Secondary outcomes: ELM and EZ; (6) Study type: randomized controlled trial. Exclusion criteria: (1) Single-arm trials; (2) Retrospective studies; (3) Studies involving animals and cells; (5) Publications in the form of reviews, guidelines, individual case reports, conference proceedings, expert opinions, editorials, technical reports, letters, etc.; (6) Duplicate studies; (7) Inaccurate, incomplete, or inaccessible data. Quality assessment Quality assessment was conducted using the Cochrane Randomized Trials Risk of Bias Assessment (10), performed by three reviewers. Each study was assessed based on six items, each of which could be graded as “low risk,” “ unclear risk,” or “high risk.” If all six items were graded as “low risk,” the study was considered to be of high quality. If any item was graded as “high risk,” the study was considered to be of lower quality. If the two members disagreed on the grading of the same item, a senior third party made the final decision. The risk of bias plots and risk of bias summaries were created using Review Manager software (version 5.3, Cochrane RevMan, London, UK). Data extraction Two staff members independently extracted the basic information from the included studies after reading the full text of the articles. The basic information included: first author, year, group, gender ratio, age, MH duration, MH diameter, MH index, lens status, and geographic region. Data collection also included primary and secondary outcomes. For anatomical closure rate, the number of successful closures per group was collected. For mean BCVA, Logarithm of the Minimum Angle of Resolution (logMAR) values were collected in the form of mean ± SD. If the study only reported the median (min-max), the method of Luo et al.(11) and Wan et al.(12) was used to convert it to mean ± SD. For ELM and EZ, the number of recoveries per group was collected. Statistical analysis Forest plots were plotted using Review Manager software (version 5.3, Cochrane RevMan, London, UK) for analysis. For dichotomous variables, the relative risk (RR) was calculated, and for continuous variables, the mean difference (MD) was calculated. when P < 0.05 was considered statistically significant. 95% confidence intervals (95% CI) were calculated to assess the reliability of the results. Heterogeneity analysis results were determined based on the results of the I² test. When I² 0.05, heterogeneity was low, and a fixed-effect model was used. When I² >50% and P < 0.05, significant heterogeneity was present, and a random-effects model was used. Bias analysis and sensitivity analysis were performed using Stata software (version 12, Stata Corporation, Lakewood Drive, Texas, USA). Bias analysis utilized Begg’s test and Egger’s test. When P < 0.05 , there was a risk of bias. Sensitivity analysis employed the one-by-one exclusion method. Results The results of literature retrieval A total of 202 relevant publications was identified through systematic searching. Based on the inclusion and exclusion criteria, 10 studies were finally included. The specific processes and results of literature screening were presented as a flow chart in Figure 1. Basic features and quality assessment of the included studies A total of 649 patients participated in the 10 studies included in this review. Most of the patients were over 60 years old, and there were more female patients than male patients. Among them, 306 patients underwent traditional ILM peeling surgery, and 343 patients underwent ILM flap surgery. Detailed basic information about the patients is shown in Table 1. All 10 of these studies were RCTs and provided detailed descriptions of the randomization methods. The Baskaran et al. study had a higher proportion of female patients and did not exclude the effects of diabetes and hypertension on MH. Additionally, this study had a high rate of loss to follow-up, which may have influenced the results (13). The studies by Fathy et al., Iovino et al., and Michalewska et al. did not mention how double-blinding was conducted (4, 14, 15). The Leisser et al. study not only failed to mention the double-blinding setup but also had fewer than 20 patients (16). In the Kannan et al. study, the authors themselves performed all surgeries (17). The studies by Agrawal et al., Ehrhardt et al., Montoya et al., and Ventre et al. had higher quality (18-21). The specific results are shown in Figure 2. Outcomes of meta-analysis Anatomical closure rate There were 8 studies reporting anatomical closure rate outcomes. I 2 = 0% and P = 0.46, therefore a fixed-effects model was chosen. RR was 0.92, with a 95% CI ranging from 0.86 to 0.98, and P = 0.007, indicating that the closure rate was significantly higher in the inverted ILM flap group (InFlap) compared to the traditional ILM peeling group (ILM peeling). In the < 600 μm subgroup, there was no statistically significant difference in closure rates between ILM peeling and InFlap. In the ≥ 600 μm subgroup, the closure rate was significantly higher with InFlap (Figure 3). Mean BCVA There were 7 studies reporting anatomical closure rate outcomes. I 2 = 88% and P < 0.00001, therefore a random-effects model was chosen. MD was 0.02, with a 95% CI ranging from -0.08 to 0.13, and P = 0.65, indicating no statistically significant difference in closure rates between ILM peeling and InFlap in terms of mean BCVA. There was no significant difference in mean BCVA between ILM peeling and InFlap in either the <600 μm subgroup or the ≥600 μm subgroup (Figure 4A). Agrawal et al. and Baskaran et al. reported BCVA data at 3 months, 6 months, and 12 months postoperatively, and these data were included in the subgroup analysis. I 2 = 89% and P < 0.00001, therefore a random-effects model was chosen. MD was 0.04, with a 95% CI ranging from -0.01 to 0.09, and P = 0.16, indicating no statistically significant difference in closure rates between ILM peeling and InFlap in terms of mean BCVA. There was no significant difference in mean BCVA between ILM peeling and InFlap in the 3-month subgroup, 6-month subgroup, or 12-month subgroup (Figure 4B). ELM and EZ There were 4 studies reporting ELM. I 2 = 12% and P = 0.33, therefore a fixed-effects model was chosen. RR was 1.29, with a 95% CI ranging from 1.08 to 1.53, and P = 0.004, indicating that the ELM was significantly higher in the ILM peeling compared to the InFlap. And also, ILM peeling was higher than InFlap in either the <600 μm subgroup or the ≥600 μm subgroup (Figure 5A). There were 4 studies reporting EZ. I 2 = 0% and P = 0.80, therefore a fixed-effects model was chosen. RR was 1.47, with a 95% CI ranging from 1.05 to 2.07, and P = 0.03, indicating that the EZ was significantly higher in the ILM peeling compared to the InFlap. However, there was no significant difference in EZ between ILM peeling and InFlap in either the <600 μm subgroup or the ≥600 μm subgroup (Figure 5B). Reporting bias The results of Begg’s test and Egger’s test for anatomical closure rate, mean BCVA, ELM and EZ were P = 0.621 and P = 0.475, P = 0.652 and P = 0.550, P = 0.174 and P = 0.081, and P = 0.497 and P = 0.795, respectively. These results indicated that there was no significant publication bias for any of the outcomes in the included literature. Sensitivity analysis Sensitivity analyses were performed for each outcome data (Table 2). For mean BCVA, the combined results of the remaining study data remained unchanged after one-by-one exclusion of all studies, indicating robust results. For closure rate, after excluding the studies of Agrawal 2022, the pooled results of the remaining 7 studies showed no significant difference in closure rate between ILM peeling and InFlap. For ELM, after excluding the studies of Ventre 2022, the pooled results of the remaining 3 studies showed no significant difference in ELM between ILM peeling and InFlap. For EZ, after excluding the studies by Ventre 2022 or Iovino 2018, the pooled results of the remaining 3 studies showed that there was no significant difference between ILM peeling and InFlap in terms of EZ. Discussion Our results show that for large-diameter MHs greater than 600 µm, the inverted ILM flap technique significantly increases the closure rate. However, both ILM peeling and the inverted ILM flap technique can improve patient vision. In terms of OCT parameters, the ILM peeling technique may be more beneficial for ELM and EZ recovery. The discussion on ILM peeling and inverted ILM flap techniques in MH surgery has been ongoing for over a decade. The principle behind the inverted ILM flap promoting MH closure is that the inverted ILM flap serves as a scaffold, facilitating Müller cell glial proliferation (22). A recent study once again demonstrated that the inverted ILM flap technique can increase closure rates (23, 24), consistent with our results. However, this study did not include MH diameter as a grouping factor, reducing the reliability of its results. Moreover, other studies have shown that ILM peeling and inverted ILM flap techniques yield no significant differences in MH closure and visual improvement for MHs ≤ 400 µm (24, 25), which remains consistent with our findings. The two studies included literature not limited to RCTs, while our results are restricted to RCTs. Overall, for MH ≤ 600 µm, these two surgical approaches can be selected based on actual circumstances. In previous meta-analyses comparing ILM peeling with inverted ILM flap techniques, little attention has been paid to OCT parameters. In actual clinical practice, it has been found that changes in ELM and EZ cannot be ignored in terms of their impact on postoperative visual acuity in patients (26). Our results seem to indicate that patients who underwent ILM stripping had higher ELM and EZ recovery rates. However, in this study, since we did not include non-RCT studies, there were only four RCT studies that examined ELM and EZ. After performing a sensitivity analysis, we found that the ELM and EZ results may be unstable, and that individual studies have a significant impact on the combined results, especially the EZ results. It is interesting to note that in our results, there was no significant difference in visual recovery between the ILM peeling and inverted ILM flap groups, regardless of MH diameter. Sensitivity analysis also revealed that the results were highly stable. However, Tzoumas et al. observed better visual recovery in the inverted ILM flap group, which is inconsistent with our findings (5). Akhtar et al. observed that in the subgroup with RCT > 400 µm, patients in the ILM flap technique group had better postoperative visual recovery, which also differs from our results (6). Future studies may require more RCT data to clarify the effects of inverted ILM flap technique on postoperative visual acuity and OCT parameters. Limitations There are some limitations in the present meta-analysis. First, the treatment efficacy may be affected by climate, economy, food culture and other factors, and not fully applicable to CRC patients from China or around the world, due to the fact that the included studies are all in English, and the samples are all from countries and regions in Europe and the United States. Second, all included studies were RCTs, and the number of studies was relatively small, especially with only four papers related to OCT parameters. Conclusions In summary, for MHs with a diameter greater than 600 µm, the inverted ILM flap technique can significantly improve anatomical closure rates. However, the ILM peeling technique may be more beneficial for the recovery of ELM and EZ. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing interests The authors declare that they have no competing interests. Funding There are no funders to report for this submission Authors' contributions Q.T. designed the study, conducted formal analysis and investigation, and wrote the main manuscript text. H.W. performed data curation, participated in investigation, and prepared visualizations. XZ.Z. validated the data, assisted with manuscript drafting, and revised the content. ZM.Y. supervised the study, managed project administration, and critically reviewed the manuscript. All authors reviewed and approved the final manuscript. Acknowledgements Not applicable. References Zhang XT, Wang JX, Chen S. Clinical observation of vitrectomy combined with endolaser photocoagulation at the edge of posterior scleral staphyloma for macular hole retinal detachment in high myopia. International journal of ophthalmology. 2022;15(10):1650-6. Lee YM, Bahrami B, Selva D, Casson RJ, Chan WO. Scoping review of nonsurgical treatment options for macular holes. Survey of ophthalmology. 2024;69(5):677-96. Macchi I, Huelin FJ, Young-Zvandasara T, Di Simplicio S, Kadhim MR, Chawla H, et al. PEDICLE TRANSPOSITION FLAP, INVERTED FLAP, FREE FLAP, AND STANDARD PEEL FOR LARGE FULL-THICKNESS MACULAR HOLES: A Comparative Study. Retina (Philadelphia, Pa). 2024;44(9):1552-9. Michalewska Z, Michalewski J, Adelman RA, Nawrocki J. Inverted internal limiting membrane flap technique for large macular holes. Ophthalmology. 2010;117(10):2018-25. Tzoumas N, McNally TW, Teh BL, Zaman M, Yorston D, Lois N, et al. Internal Limiting Membrane Flaps in Macular Hole Surgery: A Systematic Review and Individual Participant Data Meta-analysis. Ophthalmology Retina. 2025;9(8):717-30. Akhtar SMM, Saleem SZ, Rizvi SAA, Fareed A, Mumtaz M, Saleem S, et al. Critical analysis of macular hole repair techniques: a comprehensive systematic review and meta-analysis comparing internal limiting membrane flap and internal limiting membrane peeling for any size of macular hole. BMC ophthalmology. 2025;25(1):174. Wang M, Yu Y, Wang Z, Liang X, Liu W. Surgical Treatment for Traumatic Macular Holes: Reconstructive Changes in Foveal Microstructures and Visual Predictors Analysis. Ophthalmologica Journal international d'ophtalmologie International journal of ophthalmology Zeitschrift fur Augenheilkunde. 2021;244(4):339-46. Joo JH, Nam WH, Joo T, Moon SW. Role of intraretinal cysts in the prediction of postoperative closure and photoreceptor damages of the idiopathic full-thickness macular hole. BMC ophthalmology. 2022;22(1):5. Kitao M, Wakabayashi T, Nishida K, Sakaguchi H, Nishida K. Long-term reconstruction of foveal microstructure and visual acuity after idiopathic macular hole repair: three-year follow-up study. The British journal of ophthalmology. 2019;103(2):238-44. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed). 2011;343:d5928. Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Statistical methods in medical research. 2018;27(6):1785-805. Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC medical research methodology. 2014;14:135. Baskaran P, Sindal MD, Ganne P, Madanagopalan VG, Krishnappa NC, Rajendran A, et al. Closure rate and recovery of subfoveal microstructures following conventional internal limiting membrane peeling versus per fluoro octane-assisted inverted flap for large macular holes - A randomized controlled trial (InFlap Study). Indian journal of ophthalmology. 2024;72(Suppl 1):S75-s83. Fathy K, Magdy A, Shama A, Souka A. Anatomical outcome of temporal inverted flap technique versus conventional internal limiting membrane peeling for large macular hole treatment. Alexandria Journal of Medicine. 2024;60(1):327-35. Iovino C, Caminiti G, Miccoli M, Nasini F, Casini G, Peiretti E. Comparison of inverted flap and subretinal aspiration technique in full-thickness macular hole surgery: a randomized controlled study. European journal of ophthalmology. 2018;28(3):324-8. Leisser C, Ruiss M, Pilwachs C, Findl O. ILM peeling with ILM flap transposition vs. classic ILM peeling for small and medium macula holes-a prospective randomized trial. Spektrum der Augenheilkunde : Zeitschrift der Osterreichischen Ophthalmologischen Gesellschaft, OOG. 2023;37(1):9-14. Kannan NB, Kohli P, Parida H, Adenuga OO, Ramasamy K. Comparative study of inverted internal limiting membrane (ILM) flap and ILM peeling technique in large macular holes: a randomized-control trial. BMC ophthalmology. 2018;18(1):177. Agrawal V, Jindal K, Dhakad Y, Rathore P, Khilnani K. Multilayered inverted internal limiting membrane flap technique versus standard internal limiting membrane peeling for large macular holes: A comparative study. Indian journal of ophthalmology. 2022;70(3):909-13. Ehrhardt A, Delpuech M, Luc A, Zessler A, Pastor G, Angioi-Duprez K, et al. Dissociated Optic Nerve Fiber Layer Appearance after Macular Hole Surgery: A Randomized Controlled Trial Comparing the Temporal Inverted Internal Limiting Membrane Flap Technique with Conventional Peeling. Ophthalmology Retina. 2023;7(3):227-35. Velez-Montoya R, Ramirez-Estudillo JA, Sjoholm-Gomez de Liano C, Bejar-Cornejo F, Sanchez-Ramos J, Guerrero-Naranjo JL, et al. Inverted ILM flap, free ILM flap and conventional ILM peeling for large macular holes. International journal of retina and vitreous. 2018;4:8. Ventre L, Fallico M, Longo A, Parisi G, Russo A, Bonfiglio V, et al. CONVENTIONAL INTERNAL LIMITING MEMBRANE PEELING VERSUS INVERTED FLAP FOR SMALL-TO-MEDIUM IDIOPATHIC MACULAR HOLE: A Randomized Trial. Retina (Philadelphia, Pa). 2022;42(12):2251-7. Morawski K, Kocemba-Pilarczyk K, Zarzycka M, Dudzik P, Trojan SE, Laidler P. In vitro culture Muller cell model to study the role of inverted internal limiting membrane flap technique in macular hole closure. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 2021;72(3). Reynaldo, Garyudanefi N, Susetyo PB. Comparison of ILM peeling vs. inverted ILM flap for macular hole closure and visual outcomes: systematic review and meta-analysis. International journal of retina and vitreous. 2025;11(1):81. Li P, Li L, Wu J. Inverted Internal Limiting Membrane Flap versus Internal Limiting Membrane Peeling for <400 μm Macular Hole: A Meta-Analysis and Systematic Review. Ophthalmic research. 2023;66(1):1342-52. Lee SM, Lee JW, Lee JE, Choi HY, Lee JS, Byon I. Efficacy of inverted inner limiting membrane flap technique for macular holes of ≤400 μm: A systematic review and meta-analysis. PloS one. 2024;19(4):e0302481. Elhusseiny AM, Schwartz SG, Flynn HW, Jr., Smiddy WE. Long-Term Outcomes after Macular Hole Surgery. Ophthalmology Retina. 2020;4(4):369-76. Tables Tables 1 and 2 are available in the Supplementary Files section Additional Declarations No competing interests reported. Supplementary Files Checklistitemsupplementarytable1.docx SearchStrategysupplementarytable2.docx table1.docx table2.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviews received at journal 21 May, 2026 Reviewers agreed at journal 15 May, 2026 Reviews received at journal 19 Nov, 2025 Reviewers agreed at journal 18 Nov, 2025 Reviewers invited by journal 17 Nov, 2025 Editor invited by journal 24 Oct, 2025 Editor assigned by journal 23 Oct, 2025 Submission checks completed at journal 23 Oct, 2025 First submitted to journal 22 Oct, 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. 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1","display":"","copyAsset":false,"role":"figure","size":108011,"visible":true,"origin":"","legend":"\u003cp\u003eA flowchart of the literature searching and screening\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7927324/v1/c81ab23bdf8be3a0603a4008.jpg"},{"id":96967518,"identity":"cf8521df-07bd-4b62-92fd-674ebc2e2538","added_by":"auto","created_at":"2025-11-28 06:55:20","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":130249,"visible":true,"origin":"","legend":"\u003cp\u003eA summaries of bias risk assessments for included studies. (A) Graph on risk of bias. (B) Summary for risk of bias.\u003c/p\u003e","description":"","filename":"Fig2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7927324/v1/1985987195d7e728a4b0eeed.jpg"},{"id":97137387,"identity":"392c9792-0a6e-48d3-8531-79f25fb284c9","added_by":"auto","created_at":"2025-12-01 09:57:41","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":119670,"visible":true,"origin":"","legend":"\u003cp\u003ePooled analysis of anatomical closure rate. MH minimum diameter as a grouping factor.\u003c/p\u003e","description":"","filename":"Fig3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7927324/v1/95c0bf1faa738af2c2dde3ea.jpg"},{"id":96967530,"identity":"590a24db-fb7f-4c15-95e5-6b709d981f3c","added_by":"auto","created_at":"2025-11-28 06:55:20","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":242499,"visible":true,"origin":"","legend":"\u003cp\u003ePooled analysis of mean BCVA. (A) MH minimum diameter as a grouping factor. (B) Follow-up time as a sub-licensing factor. BCVA: Best-corrected visual acuity.\u003c/p\u003e","description":"","filename":"Fig4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7927324/v1/ae7eccb122b3df7e80ba1eb8.jpg"},{"id":97137694,"identity":"f806de65-aafe-439c-b7d0-0f031434a802","added_by":"auto","created_at":"2025-12-01 09:58:04","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":176367,"visible":true,"origin":"","legend":"\u003cp\u003ePooled analysis of ELM (A) and EZ (B). MH minimum diameter as a grouping factor. ELM: External limiting membrane. EZ: Ellipsoid zone.\u003c/p\u003e","description":"","filename":"Fig5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7927324/v1/098ea48caeaec5ff4f42c206.jpg"},{"id":97249203,"identity":"42291654-53fe-43f3-b547-c7026adb26d5","added_by":"auto","created_at":"2025-12-02 13:11:15","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1377937,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7927324/v1/e7af1b11-f6b1-466f-9a6b-52572b343be1.pdf"},{"id":96967522,"identity":"bb91120a-5b6a-45e8-88b2-c732f5e044fe","added_by":"auto","created_at":"2025-11-28 06:55:20","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":33539,"visible":true,"origin":"","legend":"","description":"","filename":"Checklistitemsupplementarytable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7927324/v1/6d76db4dbd5033537eb0983d.docx"},{"id":96967528,"identity":"b9a22588-7dae-4efc-9d07-3403a84f930a","added_by":"auto","created_at":"2025-11-28 06:55:20","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":14695,"visible":true,"origin":"","legend":"","description":"","filename":"SearchStrategysupplementarytable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7927324/v1/0eec1b0b54f441c23ae6b6e5.docx"},{"id":97136238,"identity":"42dc7eab-39c3-47f4-9e21-e2831ba2ce8c","added_by":"auto","created_at":"2025-12-01 09:56:10","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":26906,"visible":true,"origin":"","legend":"","description":"","filename":"table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7927324/v1/384778257936e766774aa66e.docx"},{"id":96967533,"identity":"b0829c2d-21c6-495e-9a37-f806511fbb61","added_by":"auto","created_at":"2025-11-28 06:55:20","extension":"docx","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":14582,"visible":true,"origin":"","legend":"","description":"","filename":"table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7927324/v1/a3b01d666f67a73e476dee54.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of inverted inner limiting membrane flap technique and traditional peeling for visual recovery and microscopic structural improvement in patients with macular holes: a meta-analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eMacular hole (MH) is a retinal disease that poses a serious threat to vision. It generally refers to a defect in the neural retina at the center of the macular area. the formation of MH leads to symptoms such as decreased central vision, distorted vision, and central scotoma, causing a massive impairment of visual function, and is difficult and risky to treat (1). Currently, inner limiting membrane (ILM) peeling vitrectomy remains the gold standard for treating MH (2). A retrospective study found that for patients with larger hole diameters, the anatomical success rate of traditional ILM peeling drops to 60% (3). A well-known fact is that MH is classified into three categories based on diameter: small holes (\u0026le;\u0026thinsp;250 \u0026micro;m), medium holes (\u0026gt;\u0026thinsp;250 \u0026micro;m, \u0026le; 400 \u0026micro;m), and large holes (\u0026gt;\u0026thinsp;400 \u0026micro;m). Michalewska et al. were the first to modify the standard MH surgery, improving visual function and anatomical outcomes in patients with \u0026gt;\u0026thinsp;400 \u0026micro;m holes. The modified surgery is called the inverted ILM flap technique (4).\u003c/p\u003e\u003cp\u003eWith the widespread application of the inverted ILM flap technique, the number of supporting literature has been increasing (5, 6). However, a notable issue remains: when using traditional ILM peeling techniques to treat MHs with a diameter\u0026thinsp;\u0026gt;\u0026thinsp;400 \u0026micro;m, although the surgical success rate may not reach 100%, most tears can still be closed; the true risk of surgical failure may lie in certain larger-diameter MHs (e.g., exceeding 600 \u0026micro;m). For such large-diameter MHs, which is superior: traditional ILM peeling technique or modified ILM flap coverage technique? To date, there is still no authoritative conclusion on this matter.\u003c/p\u003e\u003cp\u003eThe primary outcomes assessed after MH surgery include anatomical closure and best-corrected visual acuity (BCVA). BCVA may be related to foveal microstructures (7). In recent years, optical coherence tomography (OCT) has been widely used for the diagnosis and prognosis of MH. OCT parameters, such as the external limiting membrane (ELM) and ellipsoid zone (EZ), have also been used to predict postoperative visual acuity (8, 9). However, there are relatively few meta-analyses focusing on postoperative OCT parameters in MH patients.\u003c/p\u003e\u003cp\u003eIn this study, we collected randomized controlled clinical trials (RCTs) comparing ILM peeling vs. inverted ILM flap techniques for the treatment of MH. Patients were divided into two subgroups based on the minimum MH diameter: \u0026le; 600 micrometers and \u0026gt;\u0026thinsp;600 micrometers. We assessed postoperative anatomical closure rates, BCVA, and OCT parameters, including the ELM and EZ. This study provides evidence-based medical evidence to address the question of which technique\u0026mdash;ILM peeling or inverted ILM flap\u0026mdash;is superior in MH surgery.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eLiterature retrieval\u003c/h2\u003e\u003cp\u003eAccording to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement, published studies about randomized controlled trials were retrieved from public databases including Cochrane Library and PubMed. The publication time started from the beginning of the establishment of the library to June 30, 2025, and the language of the searched articles was English. In addition, to avoid omitting any studies, we carefully searched the references of the included articles as a supplement. Included literature was screened according to the PRISMA 2020 protocol (PRISMA Checklist, Supplementary Table\u0026nbsp;1). First, following the PICOS (Population, Intervention, Comparison, Outcome, Study design) principle, two members conducted an initial screening of the articles using a combination of MeSH and free-text search terms (search strategy, Supplementary Table\u0026nbsp;2). If the two members disagreed on the inclusion of the same article, a senior third party made the final decision.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eLiterature screening\u003c/h3\u003e\n\u003cp\u003eInclusion criteria: (1) Population: MH patients; (2) Intervention: inverted ILM flap technique; (3) Control: traditional ILM peeling technique; (4) Primary outcomes: anatomical closure rate and BCVA; (5) Secondary outcomes: ELM and EZ; (6) Study type: randomized controlled trial.\u003c/p\u003e\u003cp\u003e Exclusion criteria: (1) Single-arm trials; (2) Retrospective studies; (3) Studies involving animals and cells; (5) Publications in the form of reviews, guidelines, individual case reports, conference proceedings, expert opinions, editorials, technical reports, letters, etc.; (6) Duplicate studies; (7) Inaccurate, incomplete, or inaccessible data.\u003c/p\u003e\n\u003ch3\u003eQuality assessment\u003c/h3\u003e\n\u003cp\u003e Quality assessment was conducted using the Cochrane Randomized Trials Risk of Bias Assessment (10), performed by three reviewers. Each study was assessed based on six items, each of which could be graded as \u0026ldquo;low risk,\u0026rdquo; \u0026ldquo; unclear risk,\u0026rdquo; or \u0026ldquo;high risk.\u0026rdquo; If all six items were graded as \u0026ldquo;low risk,\u0026rdquo; the study was considered to be of high quality. If any item was graded as \u0026ldquo;high risk,\u0026rdquo; the study was considered to be of lower quality. If the two members disagreed on the grading of the same item, a senior third party made the final decision. The risk of bias plots and risk of bias summaries were created using Review Manager software (version 5.3, Cochrane RevMan, London, UK).\u003c/p\u003e\n\u003ch3\u003eData extraction\u003c/h3\u003e\n\u003cp\u003eTwo staff members independently extracted the basic information from the included studies after reading the full text of the articles. The basic information included: first author, year, group, gender ratio, age, MH duration, MH diameter, MH index, lens status, and geographic region. Data collection also included primary and secondary outcomes. For anatomical closure rate, the number of successful closures per group was collected. For mean BCVA, Logarithm of the Minimum Angle of Resolution (logMAR) values were collected in the form of mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. If the study only reported the median (min-max), the method of Luo et al.(11) and Wan et al.(12) was used to convert it to mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD. For ELM and EZ, the number of recoveries per group was collected.\u003c/p\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eForest plots were plotted using Review Manager software (version 5.3, Cochrane RevMan, London, UK) for analysis. For dichotomous variables, the relative risk (RR) was calculated, and for continuous variables, the mean difference (MD) was calculated. when \u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/em\u003e was considered statistically significant. 95% confidence intervals (95% CI) were calculated to assess the reliability of the results. Heterogeneity analysis results were determined based on the results of the I\u0026sup2; test. When I\u0026sup2; \u0026lt; 50% and P\u0026thinsp;\u0026gt;\u0026thinsp;0.05, heterogeneity was low, and a fixed-effect model was used. When I\u0026sup2; \u0026gt;50% and P\u0026thinsp;\u0026lt;\u0026thinsp;0.05, significant heterogeneity was present, and a random-effects model was used. Bias analysis and sensitivity analysis were performed using Stata software (version 12, Stata Corporation, Lakewood Drive, Texas, USA). Bias analysis utilized Begg\u0026rsquo;s test and Egger\u0026rsquo;s test. When \u003cem\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.05\u003c/em\u003e, there was a risk of bias. Sensitivity analysis employed the one-by-one exclusion method.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eThe results of literature retrieval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 202 relevant publications was identified through systematic searching. Based on the inclusion and exclusion criteria, 10 studies were finally included. The specific processes and results of literature screening were presented as a flow chart in Figure 1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBasic features and quality assessment of the included studies\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 649 patients participated in the 10 studies included in this review. Most of the patients were over 60 years old, and there were more female patients than male patients. Among them, 306 patients underwent traditional ILM peeling surgery, and 343 patients underwent ILM flap surgery. Detailed basic information about the patients is shown in Table 1.\u003c/p\u003e\n\u003cp\u003eAll 10 of these studies were RCTs and provided detailed descriptions of the randomization methods. The Baskaran et al. study had a higher proportion of female patients and did not exclude the effects of diabetes and hypertension on MH. Additionally, this study had a high rate of loss to follow-up, which may have influenced the results (13). The studies by Fathy et al., Iovino et al., and Michalewska et al. did not mention how double-blinding was conducted (4, 14, 15). The Leisser et al. study not only failed to mention the double-blinding setup but also had fewer than 20 patients (16). In the Kannan et al. study, the authors themselves performed all surgeries (17). The studies by Agrawal et al., Ehrhardt et al., Montoya et al., and Ventre et al. had higher quality (18-21). The specific results are shown in Figure 2.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcomes of meta-analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnatomical closure rate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were 8 studies reporting anatomical closure rate outcomes. I\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e= 0% and \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.46, therefore a fixed-effects model was chosen. RR was 0.92, with a 95% CI ranging from 0.86 to 0.98, and P = 0.007, indicating that the closure rate was significantly higher in the inverted ILM flap group (InFlap) compared to the traditional ILM peeling group (ILM peeling). In the \u0026lt; 600 μm subgroup, there was no statistically significant difference in closure rates between ILM peeling and InFlap. In the ≥ 600 μm subgroup, the closure rate was significantly higher with InFlap (Figure 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMean BCVA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were 7 studies reporting anatomical closure rate outcomes. I\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e= 88% and \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.00001, therefore a random-effects model was chosen. MD was 0.02, with a 95% CI ranging from -0.08 to 0.13, and P = 0.65, indicating no statistically significant difference in closure rates between ILM peeling and InFlap in terms of mean BCVA. There was no significant difference in mean BCVA between ILM peeling and InFlap in either the \u0026lt;600 μm subgroup or the ≥600 μm subgroup (Figure 4A).\u003c/p\u003e\n\u003cp\u003eAgrawal et al. and Baskaran et al. reported BCVA data at 3 months, 6 months, and 12 months postoperatively, and these data were included in the subgroup analysis. I\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e= 89% and \u003cem\u003eP\u0026nbsp;\u003c/em\u003e\u0026lt; 0.00001, therefore a random-effects model was chosen. MD was 0.04, with a 95% CI ranging from -0.01 to 0.09, and P = 0.16, indicating no statistically significant difference in closure rates between ILM peeling and InFlap in terms of mean BCVA. There was no significant difference in mean BCVA between ILM peeling and InFlap in the 3-month subgroup, 6-month subgroup, or 12-month subgroup (Figure 4B).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eELM and EZ\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere were 4 studies reporting ELM. I\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e= 12% and \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.33, therefore a fixed-effects model was chosen. RR was 1.29, with a 95% CI ranging from 1.08 to 1.53, and P = 0.004, indicating that the ELM was significantly higher in the ILM peeling compared to the InFlap. And also, ILM peeling was higher than InFlap in either the \u0026lt;600 μm subgroup or the ≥600 μm subgroup (Figure 5A).\u003c/p\u003e\n\u003cp\u003eThere were 4 studies reporting EZ. I\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e= 0% and \u003cem\u003eP\u0026nbsp;\u003c/em\u003e= 0.80, therefore a fixed-effects model was chosen. RR was 1.47, with a 95% CI ranging from 1.05 to 2.07, and P = 0.03, indicating that the EZ was significantly higher in the ILM peeling compared to the InFlap. However, there was no significant difference in EZ between ILM peeling and InFlap in either the \u0026lt;600 μm subgroup or the ≥600 μm subgroup (Figure 5B).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eReporting bias\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results of Begg’s test and Egger’s test for anatomical closure rate, mean BCVA, ELM and EZ were \u003cem\u003eP\u003c/em\u003e = 0.621 and \u003cem\u003eP\u003c/em\u003e = 0.475, \u003cem\u003eP\u003c/em\u003e = 0.652 and \u003cem\u003eP\u003c/em\u003e = 0.550, \u003cem\u003eP\u003c/em\u003e = 0.174 and \u003cem\u003eP\u003c/em\u003e = 0.081, and \u003cem\u003eP\u003c/em\u003e = 0.497 and \u003cem\u003eP\u003c/em\u003e = 0.795, respectively. These results indicated that there was no significant publication bias for any of the outcomes in the included literature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSensitivity analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSensitivity analyses were performed for each outcome data (Table 2). For mean BCVA, the combined results of the remaining study data remained unchanged after one-by-one exclusion of all studies, indicating robust results. For closure rate, after excluding the studies of Agrawal 2022, the pooled results of the remaining 7 studies showed no significant difference in closure rate between ILM peeling and InFlap. For ELM, after excluding the studies of Ventre 2022, the pooled results of the remaining 3 studies showed no significant difference in ELM between ILM peeling and InFlap. For EZ, after excluding the studies by Ventre 2022 or Iovino 2018, the pooled results of the remaining 3 studies showed that there was no significant difference between ILM peeling and InFlap in terms of EZ.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur results show that for large-diameter MHs greater than 600 \u0026micro;m, the inverted ILM flap technique significantly increases the closure rate. However, both ILM peeling and the inverted ILM flap technique can improve patient vision. In terms of OCT parameters, the ILM peeling technique may be more beneficial for ELM and EZ recovery.\u003c/p\u003e\u003cp\u003eThe discussion on ILM peeling and inverted ILM flap techniques in MH surgery has been ongoing for over a decade. The principle behind the inverted ILM flap promoting MH closure is that the inverted ILM flap serves as a scaffold, facilitating M\u0026uuml;ller cell glial proliferation (22). A recent study once again demonstrated that the inverted ILM flap technique can increase closure rates (23, 24), consistent with our results. However, this study did not include MH diameter as a grouping factor, reducing the reliability of its results. Moreover, other studies have shown that ILM peeling and inverted ILM flap techniques yield no significant differences in MH closure and visual improvement for MHs\u0026thinsp;\u0026le;\u0026thinsp;400 \u0026micro;m (24, 25), which remains consistent with our findings. The two studies included literature not limited to RCTs, while our results are restricted to RCTs. Overall, for MH\u0026thinsp;\u0026le;\u0026thinsp;600 \u0026micro;m, these two surgical approaches can be selected based on actual circumstances.\u003c/p\u003e\u003cp\u003eIn previous meta-analyses comparing ILM peeling with inverted ILM flap techniques, little attention has been paid to OCT parameters. In actual clinical practice, it has been found that changes in ELM and EZ cannot be ignored in terms of their impact on postoperative visual acuity in patients (26). Our results seem to indicate that patients who underwent ILM stripping had higher ELM and EZ recovery rates. However, in this study, since we did not include non-RCT studies, there were only four RCT studies that examined ELM and EZ. After performing a sensitivity analysis, we found that the ELM and EZ results may be unstable, and that individual studies have a significant impact on the combined results, especially the EZ results.\u003c/p\u003e\u003cp\u003eIt is interesting to note that in our results, there was no significant difference in visual recovery between the ILM peeling and inverted ILM flap groups, regardless of MH diameter. Sensitivity analysis also revealed that the results were highly stable. However, Tzoumas et al. observed better visual recovery in the inverted ILM flap group, which is inconsistent with our findings (5). Akhtar et al. observed that in the subgroup with RCT\u0026thinsp;\u0026gt;\u0026thinsp;400 \u0026micro;m, patients in the ILM flap technique group had better postoperative visual recovery, which also differs from our results (6). Future studies may require more RCT data to clarify the effects of inverted ILM flap technique on postoperative visual acuity and OCT parameters.\u003c/p\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eThere are some limitations in the present meta-analysis. First, the treatment efficacy may be affected by climate, economy, food culture and other factors, and not fully applicable to CRC patients from China or around the world, due to the fact that the included studies are all in English, and the samples are all from countries and regions in Europe and the United States. Second, all included studies were RCTs, and the number of studies was relatively small, especially with only four papers related to OCT parameters.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, for MHs with a diameter greater than 600 \u0026micro;m, the inverted ILM flap technique can significantly improve anatomical closure rates. However, the ILM peeling technique may be more beneficial for the recovery of ELM and EZ.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are no funders to report for this submission\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eQ.T. designed the study, conducted formal analysis and investigation, and wrote the main manuscript text. H.W. performed data curation, participated in investigation, and prepared visualizations. XZ.Z. validated the data, assisted with manuscript drafting, and revised the content. ZM.Y. supervised the study, managed project administration, and critically reviewed the manuscript. All authors reviewed and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZhang XT, Wang JX, Chen S. Clinical observation of vitrectomy combined with endolaser photocoagulation at the edge of posterior scleral staphyloma for macular hole retinal detachment in high myopia. International journal of ophthalmology. 2022;15(10):1650-6.\u003c/li\u003e\n\u003cli\u003eLee YM, Bahrami B, Selva D, Casson RJ, Chan WO. Scoping review of nonsurgical treatment options for macular holes. Survey of ophthalmology. 2024;69(5):677-96.\u003c/li\u003e\n\u003cli\u003eMacchi I, Huelin FJ, Young-Zvandasara T, Di Simplicio S, Kadhim MR, Chawla H, et al. PEDICLE TRANSPOSITION FLAP, INVERTED FLAP, FREE FLAP, AND STANDARD PEEL FOR LARGE FULL-THICKNESS MACULAR HOLES: A Comparative Study. Retina (Philadelphia, Pa). 2024;44(9):1552-9.\u003c/li\u003e\n\u003cli\u003eMichalewska Z, Michalewski J, Adelman RA, Nawrocki J. Inverted internal limiting membrane flap technique for large macular holes. Ophthalmology. 2010;117(10):2018-25.\u003c/li\u003e\n\u003cli\u003eTzoumas N, McNally TW, Teh BL, Zaman M, Yorston D, Lois N, et al. Internal Limiting Membrane Flaps in Macular Hole Surgery: A Systematic Review and Individual Participant Data Meta-analysis. Ophthalmology Retina. 2025;9(8):717-30.\u003c/li\u003e\n\u003cli\u003eAkhtar SMM, Saleem SZ, Rizvi SAA, Fareed A, Mumtaz M, Saleem S, et al. Critical analysis of macular hole repair techniques: a comprehensive systematic review and meta-analysis comparing internal limiting membrane flap and internal limiting membrane peeling for any size of macular hole. BMC ophthalmology. 2025;25(1):174.\u003c/li\u003e\n\u003cli\u003eWang M, Yu Y, Wang Z, Liang X, Liu W. Surgical Treatment for Traumatic Macular Holes: Reconstructive Changes in Foveal Microstructures and Visual Predictors Analysis. Ophthalmologica Journal international d\u0026apos;ophtalmologie International journal of ophthalmology Zeitschrift fur Augenheilkunde. 2021;244(4):339-46.\u003c/li\u003e\n\u003cli\u003eJoo JH, Nam WH, Joo T, Moon SW. Role of intraretinal cysts in the prediction of postoperative closure and photoreceptor damages of the idiopathic full-thickness macular hole. BMC ophthalmology. 2022;22(1):5.\u003c/li\u003e\n\u003cli\u003eKitao M, Wakabayashi T, Nishida K, Sakaguchi H, Nishida K. Long-term reconstruction of foveal microstructure and visual acuity after idiopathic macular hole repair: three-year follow-up study. The British journal of ophthalmology. 2019;103(2):238-44.\u003c/li\u003e\n\u003cli\u003eHiggins JP, Altman DG, G\u0026oslash;tzsche PC, J\u0026uuml;ni P, Moher D, Oxman AD, et al. The Cochrane Collaboration\u0026apos;s tool for assessing risk of bias in randomised trials. BMJ (Clinical research ed). 2011;343:d5928.\u003c/li\u003e\n\u003cli\u003eLuo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Statistical methods in medical research. 2018;27(6):1785-805.\u003c/li\u003e\n\u003cli\u003eWan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC medical research methodology. 2014;14:135.\u003c/li\u003e\n\u003cli\u003eBaskaran P, Sindal MD, Ganne P, Madanagopalan VG, Krishnappa NC, Rajendran A, et al. Closure rate and recovery of subfoveal microstructures following conventional internal limiting membrane peeling versus per fluoro octane-assisted inverted flap for large macular holes - A randomized controlled trial (InFlap Study). Indian journal of ophthalmology. 2024;72(Suppl 1):S75-s83.\u003c/li\u003e\n\u003cli\u003eFathy K, Magdy A, Shama A, Souka A. Anatomical outcome of temporal inverted flap technique versus conventional internal limiting membrane peeling for large macular hole treatment. Alexandria Journal of Medicine. 2024;60(1):327-35.\u003c/li\u003e\n\u003cli\u003eIovino C, Caminiti G, Miccoli M, Nasini F, Casini G, Peiretti E. Comparison of inverted flap and subretinal aspiration technique in full-thickness macular hole surgery: a randomized controlled study. European journal of ophthalmology. 2018;28(3):324-8.\u003c/li\u003e\n\u003cli\u003eLeisser C, Ruiss M, Pilwachs C, Findl O. ILM peeling with ILM flap transposition vs. classic ILM peeling for small and medium macula holes-a prospective randomized trial. Spektrum der Augenheilkunde : Zeitschrift der Osterreichischen Ophthalmologischen Gesellschaft, OOG. 2023;37(1):9-14.\u003c/li\u003e\n\u003cli\u003eKannan NB, Kohli P, Parida H, Adenuga OO, Ramasamy K. Comparative study of inverted internal limiting membrane (ILM) flap and ILM peeling technique in large macular holes: a randomized-control trial. BMC ophthalmology. 2018;18(1):177.\u003c/li\u003e\n\u003cli\u003eAgrawal V, Jindal K, Dhakad Y, Rathore P, Khilnani K. Multilayered inverted internal limiting membrane flap technique versus standard internal limiting membrane peeling for large macular holes: A comparative study. Indian journal of ophthalmology. 2022;70(3):909-13.\u003c/li\u003e\n\u003cli\u003eEhrhardt A, Delpuech M, Luc A, Zessler A, Pastor G, Angioi-Duprez K, et al. Dissociated Optic Nerve Fiber Layer Appearance after Macular Hole Surgery: A Randomized Controlled Trial Comparing the Temporal Inverted Internal Limiting Membrane Flap Technique with Conventional Peeling. Ophthalmology Retina. 2023;7(3):227-35.\u003c/li\u003e\n\u003cli\u003eVelez-Montoya R, Ramirez-Estudillo JA, Sjoholm-Gomez de Liano C, Bejar-Cornejo F, Sanchez-Ramos J, Guerrero-Naranjo JL, et al. Inverted ILM flap, free ILM flap and conventional ILM peeling for large macular holes. International journal of retina and vitreous. 2018;4:8.\u003c/li\u003e\n\u003cli\u003eVentre L, Fallico M, Longo A, Parisi G, Russo A, Bonfiglio V, et al. CONVENTIONAL INTERNAL LIMITING MEMBRANE PEELING VERSUS INVERTED FLAP FOR SMALL-TO-MEDIUM IDIOPATHIC MACULAR HOLE: A Randomized Trial. Retina (Philadelphia, Pa). 2022;42(12):2251-7.\u003c/li\u003e\n\u003cli\u003eMorawski K, Kocemba-Pilarczyk K, Zarzycka M, Dudzik P, Trojan SE, Laidler P. In vitro culture Muller cell model to study the role of inverted internal limiting membrane flap technique in macular hole closure. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society. 2021;72(3).\u003c/li\u003e\n\u003cli\u003eReynaldo, Garyudanefi N, Susetyo PB. Comparison of ILM peeling vs. inverted ILM flap for macular hole closure and visual outcomes: systematic review and meta-analysis. International journal of retina and vitreous. 2025;11(1):81.\u003c/li\u003e\n\u003cli\u003eLi P, Li L, Wu J. Inverted Internal Limiting Membrane Flap versus Internal Limiting Membrane Peeling for \u0026amp;lt;400 \u0026mu;m Macular Hole: A Meta-Analysis and Systematic Review. Ophthalmic research. 2023;66(1):1342-52.\u003c/li\u003e\n\u003cli\u003eLee SM, Lee JW, Lee JE, Choi HY, Lee JS, Byon I. Efficacy of inverted inner limiting membrane flap technique for macular holes of \u0026le;400 \u0026mu;m: A systematic review and meta-analysis. PloS one. 2024;19(4):e0302481.\u003c/li\u003e\n\u003cli\u003eElhusseiny AM, Schwartz SG, Flynn HW, Jr., Smiddy WE. Long-Term Outcomes after Macular Hole Surgery. Ophthalmology Retina. 2020;4(4):369-76.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 and 2 are available in the Supplementary Files section\u003c/p\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":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"internal limiting membrane peeling, inverted internal limiting membrane flap techniques, macular holes, diameter ≥ 600 µm, meta-analysis","lastPublishedDoi":"10.21203/rs.3.rs-7927324/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7927324/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA meta-analysis comparing the efficacy of internal limiting membrane (ILM) peeling and inverted ILM flap techniques for the treatment of macular holes (MH).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eResearchers searched the Cochrane Library and PubMed database for relevant randomized controlled trials published from the establishment of the database to June 30, 2025. The control and intervention groups were the ILM peeling group and the inverted ILM flap group, respectively. Literature quality assessment was conducted using the Cochrane Risk of Bias Assessment Tool. Meta-analysis was performed using Review Manager and Stata software. Anatomical closure rate and best-corrected visual acuity (BCVA) were used as primary outcomes. External limiting membrane (ELM) and ellipsoid zone (EZ) were used as secondary outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 202 relevant literature articles were screened, and 10 studies were ultimately included. Compared with the traditional ILM peeling group (ILM peeling), the closure rate was significantly higher in the inverted inner limiting membrane flap group (InFlap). In the ≥ 600 μm subgroup, the closure rate was significantly higher with InFlap. there was no statistically significant difference in closure rates between ILM peeling and InFlap in terms of mean BCVA. And also, ILM peeling was higher than InFlap in either the \u0026lt;600 μm subgroup or the ≥ 600 μm subgroup. the EZ was significantly higher in the ILM peeling compared to the InFlap.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor MHs with a diameter greater than 600 µm, the inverted ILM flap technique can significantly improve anatomical closure rates.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTrial registration\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eRegistration number: CRD420251139305.\u003c/p\u003e\n\u003cp\u003eThis study was registered at PROSPERO and no modifications were made.\u003c/p\u003e","manuscriptTitle":"Comparison of inverted inner limiting membrane flap technique and traditional peeling for visual recovery and microscopic structural improvement in patients with macular holes: a meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-28 06:55:15","doi":"10.21203/rs.3.rs-7927324/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2026-05-21T20:20:11+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"35223308923268257858614558468888066297","date":"2026-05-15T15:57:48+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-11-20T01:34:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"74367987145235443208855466965572322868","date":"2025-11-19T00:57:38+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-17T11:54:05+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-10-24T04:57:22+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-10-23T22:55:15+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-10-23T22:54:01+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Ophthalmology","date":"2025-10-23T01:40:30+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-ophthalmology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"boph","sideBox":"Learn more about [BMC Ophthalmology](http://bmcophthalmol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/boph","title":"BMC Ophthalmology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d94d5d20-4a68-4a31-9f00-529cfb124a2d","owner":[],"postedDate":"November 28th, 2025","published":true,"recentEditorialEvents":[{"type":"editorInvitedReview","content":"","date":"2026-05-21T20:20:11+00:00","index":82,"fulltext":""},{"type":"reviewerAgreed","content":"35223308923268257858614558468888066297","date":"2026-05-15T15:57:48+00:00","index":81,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2025-11-28T06:55:15+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-28 06:55:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7927324","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7927324","identity":"rs-7927324","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}