Impact of corneal sub-basal nerve plexus on epithelial thickness after small incision lenticule extraction (SMILE): a quantitative assessment using in vivo confocal microscopy and optical coherence tomography

Introduction

The corneal epithelium is the outermost layer of the cornea and is crucial in maintaining corneal physiological integrity and refractive characteristics. Widespread application of refractive surgeries has garnered increased attention to quantitative assessment of corneal epithelial thickness (CET) for accurate preoperative examination, surgical design, and postoperative monitoring (1-3). Specifically, CET map is preoperatively used to diagnose keratoconus based on its unique epithelial features. A clear understanding of epithelial thickness is warranted during secondary corneal refractive surgery as the first surgery may have led to epithelial thickening (2). CET measurements are widely performed using spectral-domain optical coherence tomography (SD-OCT). CET changes after multiple refractive surgeries have been reported (3-6), and they correlate with corneal keratometry, preoperative refractions, and surgical parameters. However, few studies have investigated the relationship between CET and corneal nerve changes after surgery.

Corneal nerve fibers radially enter the corneal stroma and run forward towards the ocular surface to form the sub-epithelial nerve plexus and vertically pierce Bowman’s membrane to form the sub-basal nerve plexus (SNP) (7). SNPs are commonly observed using in vivo confocal microscopy (IVCM) (8). Small incision lenticule extraction (SMILE) and femtosecond laser in situ keratomileusis (FS-LASIK) are two common laser refractive surgery techniques. SMILE removes the lenticule through a small side incision without creating a flap, protecting the corneal epithelium and nerves more effectively than FS-LASIK (9). Corneal denervation due to SMILE is not a major complication but may influence postoperative functional recovery (10). However, few studies have comprehensively investigated the actual condition of nerve regeneration after SMILE. Previous studies have focused on central corneal nerve recovery, and their results may be limited as they do not provide a full understanding of the complete nerve regeneration process (11-13). Furthermore, corneal nerves are crucial for epithelial homeostasis (14), and there are currently no clinical studies on the relationship between corneal nerves and epithelia after laser refractive surgeries. Therefore, our study aimed to investigate corneal denervation and reinnervation profiles throughout the entire cornea and explore the impact of corneal nerves on epithelia. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1887/rc).

Methods

Patients and ocular examinations

This prospective observational study recruited patients treated with SMILE for low-to-moderate myopia from March to May 2023 at Tianjin Medical University Eye Hospital. This study was approved by the ethics committee of Tianjin Medical University Eye Hospital (approval No. 2023KY-10) and was implemented according to the tenets of the Declaration of Helsinki (as revised in 2013). All patients signed the informed consent form before being enrolled.

The inclusion criteria were: age 18–50 years, spherical refraction of −6.0 to 0 diopters (D), cylindrical refraction of −2.0 to 0 D, and stable preoperative refractive power for at least 2 years. Eyes with thin corneas (central corneal thickness <480 µm) or eyes with ocular disorders, previous surgery, or trauma were excluded.

All patients received a comprehensive ocular examination, including medical history, uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), slit-lamp biomicroscopy, corneal topography (Pentacam; Oculus GmbH, Wetzlar, Germany), SD-OCT, dry eye assessment, manifest and cycloplegic refraction, funduscopic examinations, and IVCM. The study time points were: before surgery and 1 week, 1 month, and 6 months after surgery; SD-OCT, and IVCM were repeated at every time point.

We initially recruited 40 patients; however, only 78 eyes were included, as two patients had myopia only in one eye. One week postoperatively, all patients came for follow-up as scheduled. One month postoperatively, two patients (four eyes) were lost to follow-up. Six months postoperatively, another 11 patients (22 eyes) were lost to follow-up. Patients who lost to any follow-up were excluded, and finally our study included 27 patients (52 eyes) (Figure 1).

Figure 1 Eyes selection flowchart.

CET measurement

CET was measured using SD-OCT with RTVue (Optovue Inc., Fremont, CA, USA). The corneal adapter module and the “PachymetryWide” mode were applied to acquire a 9-mm diameter epithelial thickness map. The maps were automatically generated and contained the central 2 mm and three concentric (paracentral, 2–5 mm; mid-peripheral, 5–7 mm; and peripheral, 7–9 mm) regions. Every region was divided by eight meridians into temporal, superotemporal, superior, superonasal, nasal, inferonasal, inferior, and inferotemporal sections, yielding a total of 25 sections (Figure 2).

Figure 2 Schematic of epithelial thickness map sections generated by SD-OCT. The first concentric (paracentral) region possesses a 2–5 mm diameter range, the second concentric (mid-peripheral) region possesses a 5–7 mm diameter range, and the third concentric (peripheral) region possesses a 7–9 mm diameter range. The red star represents the scanning position of the confocal microscopy. The central, temporal, superior, nasal, and inferior area scanned using confocal microscopy were correspondingly included in the central, T5, S5, N5, and I5 section range of the map. T, temporal; ST, superotemporal; S, superior; SN, superonasal; N, nasal; IN, inferonasal; I, inferior; IT, inferotemporal; SD-OCT, spectral-domain optical coherence tomography.

SNP measurement

Corneas were observed using laser confocal microscopy (Heidelberg Retina Tomography III Rostock Cornea Module; Heidelberg Engineering GmbH, Heidelberg, Germany) to evaluate the SNPs. After topical anesthesia application, patients had to fix their gaze on a red light. SNPs in the central area were scanned first, followed by SNPs in the superior, inferior, temporal, and nasal areas, which were 3 mm apart from the central cornea. All the IVCM investigations were performed by an experienced examiner. Every confocal image was corresponded to a 400 µm × 400 µm area; the five areas scanned using IVCM were correspondingly included in the central, T5, S5, N5, and I5 section range of the CET map (Figure 2). All images were analyzed by a blinded examiner using ACCMetrics software (University of Manchester, Manchester, UK) (15). The seven corneal nerve parameters recorded were the following: corneal nerve fiber density (CNFD, number of fibers per mm²), corneal nerve branch density (CNBD, number of branch points on the main fibers per mm²), corneal nerve fiber length (CNFL, total length of nerves mm per mm²), corneal nerve fiber total branch density (CTBD, total number of branch points per mm²), corneal nerve fiber area (CNFA, total nerve fiber area mm² per mm²), corneal nerve fiber width (CNFW, average nerve fiber width mm per mm²), and corneal nerve fractal dimension (CNFrD, measure of corneal nerve complexity).

Surgical procedures and postoperative care

All SMILE procedures were uneventfully completed by the same practitioner (S.Z.) using VisuMax femtosecond laser (Carl Zeiss Meditec AG, Jena, Germany) and performed in accordance with those described previously (16). The principal surgical parameters were as follows: cap thickness 120 µm, optical zone 6.5–6.8 mm, lenticule edge thickness 15–30 µm, and side incision width 3 mm.

Patients were postoperatively prescribed with gatifloxacin (Otsuka, Tianjin, China) eye drops, to be administered four times per day for a week, with fluorometholone 0.1% (Santen, Shiga, Japan) eye drops to be administered four times per day while tapering the dose over 4 weeks, and with diquafosol sodium (Santen, Ishikawa, Japan) eye drops to be administered four times per day for at least 1 month.

Statistical analysis

Data were statistically analyzed using the SPSS software (version 29.0, IBM SPSS Statistics, Armonk, NY, USA). Data were presented as the mean ± standard deviation. The Snellen visual acuity was transformed to the logarithm of the minimum angle of resolution (logMAR). The Kolmogorov-Smirnov test was used to check data normality. A paired Student’s t-test was employed to compare the normally distributed results, and the Wilcoxon’s matched-pairs signed-rank test was employed for non-normally distributed results. The Kruskal-Wallis test was used to analyze nerve reduction in different areas. Pearson’s correlation was employed to investigate the association between postoperative anterior Q-value and CET. Partial correlation was adopted to examine the relationship between CET and corresponding SNP with the position factor as the control factor. A two-tailed P value <0.05 was considered statistically significant.

Results

Patient demographics and preoperative and postoperative ocular parameters

In this study, 52 eyes treated with SMILE for low-to-moderate myopia were followed up for 6 months. The patient demographics and preoperative ocular parameters are shown in Table 1. Postoperatively, UDVA (logMAR) at 1 week, 1 month, and 6 months were −0.06±0.09, −0.10±0.07, and −0.11±0.07, respectively. The UDVA increased from 1 week to 1 month (P<0.001) and became stable from 1 to 6 months (P=0.593); all eyes achieved a UDVA of 20/25 or better without postoperative complications. The refractions of spherical equivalent were −0.13±0.53 D at 1 week, −0.07±0.47 D at 1 month, and −0.10±0.43 D at 6 months; no significant differences were observed. Six months postoperatively, the anterior keratometry mean (Km) was 39.47±1.41 D, and the anterior Q-value was 0.44±0.21.

CET profile changes

Compared with the preoperative CET, the CET of the central region significantly increased 6 months postoperatively (P<0.001). In the paracentral region, the CET in all sections significantly increased 6 months postoperatively (P<0.05), whereas that in sections T2, ST2, I2, and IT2 significantly increased from 1 week postoperatively (all P<0.05). In the mid-peripheral region, CET in sections T5, IN5, I5, and IT5 significantly increased 6 months postoperatively (all P<0.05). In the peripheral region, except for sections T7 and IN7, CET significantly decreased 6 months postoperatively (all P<0.05; Figure 3). Figure 3 also shows the change in CET before surgery and 6 months after surgery. In the paracentral region, the three sections exhibiting the highest thickening were IT2, T2, and I2 (4.90, 4.73, and 4.00 µm, respectively); in the mid-peripheral region, they were I5, IT5, and T5, (2.93, 2.23, and 1.90 µm, respectively). Uneven epithelial thickening was primarily observed in the paracentral and mid-peripheral regions, with thickened temporal, inferior, and inferotemporal sections. Figure 4 shows the CET maps before and after SMILE in one eye.

Figure 3 Mean preoperative and postoperative CET (µm) in 25 map sections and the change in thickness at 6 months postoperatively. Pre, preoperative; 1 w post, 1 week postoperatively; 1 m post, 1 month postoperatively; 6 m post, 6 months postoperatively. C, central; T, temporal; ST, superotemporal; S, superior; SN, superonasal; N, nasal; IN, inferonasal; I, inferior; IT, inferotemporal; CET, corneal epithelial thickness.

Figure 4 CET maps before and after SMILE in one eye. (A) Preoperative map. (B) One-week postoperative map. (C) One-month postoperative map. (D) Six-month postoperative map. Min/max thickness indicated as */+. T, temporal; ST, superotemporal; S, superior; SN, superonasal; N, nasal; IN, inferonasal; I, inferior; IT, inferotemporal; CET, corneal epithelial thickness; SMILE, small incision lenticule extraction.

SNP profile changes

Compared with preoperative levels, most SNP parameters (except for CNFW) in the five areas significantly decreased 1 week postoperatively (all P<0.05). One month postoperatively, most SNP parameters (except for CNFW) in the central, temporal, superior, and nasal areas remained significantly lower than that before surgery (all P<0.05). Meanwhile, SNP parameters in the inferior area had almost fully recovered, with no difference in CNFD, CNBD, CTBD, CNFW, and CNFrD (all P>0.05). Six months postoperatively, most central SNP parameters (CNFD, CNBD, CNFL, CTBD, CNFA, and CNFrD), superior SNP parameters (CNFD and CNFL), and nasal SNP parameters (CNFD and CNFL) had not reached preoperative levels (all P<0.05), whereas most temporal SNP parameters (CNFD, CNBD, CNFL, CTBD, CNFA, and CNFrD) and inferior SNP parameters (CTBD, CNFA, CNFW, and CNFrD) had reached preoperative levels (all P>0.05) and inferior SNP parameters (CNFD, CNBD, and CNFL) had exceeded preoperative levels (all P<0.05) (Figure 5). Because the CNFL has been reported to be the most reliable nerve parameter (17), we selected it for a more in-depth analysis. The nerve reduction from SMILE was the initial cause of the alteration in nerve distribution; we adhered to the same definition of nerve reduction as previously reported (9). After SMILE, CNFL in the central, nasal, and superior areas reduced 1 week postoperatively (54.5%±27.9%, 46.4%±41.6%, and 42.3%±38.9%, respectively), and the central and nasal CNFL reduction was still evident 6 months postoperatively (25.6%±31.3% and 7.1%±62.3%, respectively; Table 2). While CNFL reduction in the temporal and inferior areas was relatively low 1 week postoperatively (18.7%±38.3% and 22.7%±46.0%, respectively), as a result, CNFL had completely recovered 6 months postoperatively. Figure 6 shows representative confocal images of SNP in the five areas before and after SMILE in one eye.

Figure 5 Mean preoperative and postoperative values of SNP parameters in five corneal areas. Pre, preoperative; 1 w post, 1 week postoperatively; 1 m post, 1 month postoperatively; 6 m post, 6 months postoperatively; CNFD, corneal nerve fiber density; CNBD, corneal nerve branch density; CNFL, corneal nerve fiber length; CTBD, corneal nerve fiber total branch density; CNFA, corneal nerve fiber area; CNFW, corneal nerve fiber width; CNFrD, corneal nerve fractal dimension; SNP, sub-basal nerve plexus.

Figure 6 Representative confocal microscopy images of the SNP [(A-D) represented images in the central area; (E-H) represented images in the temporal area; (I-L) represented images in the superior area; (M-P) represented images in the nasal area; (Q-T) represented images in the inferior area] before and after SMILE in one eye. Every confocal image corresponded to a 400 µm × 400 µm area. SNP, sub-basal nerve plexus; SMILE, small incision lenticule extraction.

Correlation analysis

The anterior Q-value was positively correlated with CET in the inferonasal section of the paracentral region (IN2), in the inferior section of the paracentral region (I2), and in the inferotemporal section of the paracentral region (IT2) 6 months postoperatively (IN2: r=0.293, P=0.035; I2: r=0.396, P=0.004; IT2: r=0.374, P=0.006). The anterior Q-value and CET were not correlated in other sections.

Partial correlation analysis showed that CET was positively correlated with SNP parameters 6 months postoperatively (CNFD: r=0.171, P=0.006; CNBD: r=0.137, P=0.028; CNFL: r=0.172, P=0.006; CTBD: r=0.141, P=0.024; CNFA: r=0.164, P=0.008); however, no correlations were observed 1 month postoperatively.

Discussion

SMILE has become the preferred procedure for refractive surgery because of its advantages. However, CET changes after SMILE have been reported, and they may induce refractive regression, irregular astigmatism, or increased high-order aberration (3,18). Here, CET in the central and paracentral regions significantly increased 6 months postoperatively, in agreement with previous reports (19). Furthermore, CET exhibited thickening in the inferotemporal, temporal, and inferior sections of the paracentral region, followed by the inferior and inferotemporal sections of the mid-peripheral region. Similar uneven CET changes were also reported by Zhu et al. (20), who identified the same trend in other surgeries. At the cellular level, one study (21) reported that epithelial thickening was due to increased cell layers and revealed that the cell density remained constant in every epithelial cell layer after SMILE. However, the underlying mechanisms have not yet been elucidated. Previous studies (3,6) suggested that the asymmetric epithelial thickness changes were related to changes in the corneal curvature gradient in different areas or to the Bell phenomenon.

Given the clinical application of CET measurement in our study, these uneven CET changes after SMILE for low-to-moderate myopia did not impact the postoperative visual acuity or refraction. Compared with low-to-moderate myopia correction, the degree of epithelial thickening after high myopia correction is more obvious (22). Under the similar degree of myopia, corneal refractive surgery like FS-LASIK can cause epithelial thickening more significantly than SMILE (20). Therefore, epithelial thickening induced by SMILE for low-to-moderate myopia is too subtle to affect the visual acuity. Additionally, the Q-value is the mathematical expression of corneal asphericity. Most original corneas are prolate, with negative Q-values, while corneas treated via myopic correction are modified to be more oblate, with positive Q-values. Here, anterior Q-values were altered from −0.30±0.12 to 0.44±0.21, consistent with other studies (23,24). Since postoperative oblateness may be the predominant factor in the decrease of functional vision (25), an appropriate knowledge of its influencing factors is necessary. A clinical study (26) has reported that corneal epithelial remodeling increased oblateness after transepithelial photorefractive keratectomy for myopia. Here, we explored the positive association between the anterior Q-value and CET in obviously thickened sections after SMILE, indicating that regional epithelial thickening aggravated the corneal oblateness and may compromise the visual quality. In brief, slight uneven CET changes after SMILE for low-to-moderate myopia may affect the visual quality but not visual acuity.

Corneal nerves are partly eliminated during ablation of the anterior corneal stroma in refractive surgeries. Postoperatively, patients may present with decreased corneal nerve density and length and increased nerve tortuosity, branching, and beading (27). Our study demonstrated that SNPs are non-uniformly distributed in different corneal areas before and after surgery, with the degree of non-uniformity being more pronounced in the postoperative state compared to the preoperative state. After SMILE, CNFL reduction is the most significant in the central area, which might have been due to the more pronounced loss of corneal volume in the center of the convex-shaped extracted lenticule. Central CNFL reductions of 54.5%±27.9% at 1 week postoperatively and 25.6%±31.3% at 6 months postoperatively indicated that recovery from serious nerve damage was not complete until 6 months postoperatively, in agreement with previous studies (13,21,28). Conversely, less evident nerve reduction in peripheral areas translated into faster recovery. Hou et al. (28) also reported that the SNP parameter values in peripheral areas recovered only to their preoperative level in high myopia. In our findings, for low-to-moderate myopia, SNP parameters in the inferior area had higher values than before surgery because of less procedure-associated injury. Moreover, uneven corneal denervation and reinnervation may be caused by SMILE-derived side incision, regional keratocyte repopulation (29), and uniformly distributed anatomy of corneal nerves (7). This study provides comprehensive information regarding the characteristics of SNP regeneration in different areas after SMILE.

Corneal nerve fibers terminate in the epithelia. Intra-epithelial nerve endings are intertwined with the epithelial cells, and are important for their health. When nerves are damaged, their supporting functions are altered, impairing physiological activity of the epithelia (29). For example, neurotrophic epitheliopathy, characterized by punctate epithelial erosions after LASIK, may be due to surgical denervation (30). In vitro, the corneal epithelia are partly controlled by sensory nerves that secrete neuropeptides such as substance P and nerve growth factor, which are vital for cell proliferation and differentiation (29,31). Corneal nerves may support the epithelia in vivo by releasing various neuro-mediators that can be detected in tear samples (32). The interactions between corneal nerves and epithelia are profound and complex, and a few studies related to this topic were still restricted to animal experiments or disease researches. SMILE-treated corneas do not commonly display apparent epithelial lesions, which does not necessarily imply that surgical denervation and reinnervation do not affect the epithelia. Here, CET values were high in the inferior and temporal regions 6 months postoperatively. Correspondingly, SNP parameter values were high in the inferior and temporal areas, and the CET and SNP parameters were positively correlated. Sufficient corneal reinnervation in the inferior and temporal areas may have a more beneficial effect on epithelial thickening, while corneal reinnervation with incomplete recovery in other areas remains at a safe threshold to sustain normal epithelial homeostasis in low-to-moderate myopia correction. Additionally, there was no correlation between CET and SNP parameters at 1 month postoperatively, which might have been due to the interruption of postoperative reactions. To the best of our knowledge, our study is the first to investigate the correlation between CET and SNP profile changes after SMILE from a positional structural perspective, which may explain the uneven epithelial thickening.

There are some limitations in this study. First, only patients with low-to-moderate myopia were recruited; therefore, the results may not be applicable to patients with other myopia ranges. In our clinical practice, SMILE is the preferred choice for patients with low-to-moderate myopia, and other refractive surgeries such as FS-LASIK or implantable Collamer lens implantation are preferred for patients with high myopia, as a result, there are only a few high myopia cases treated by SMILE. Second, it was difficult to confirm whether the same corneal position was investigated at each follow-up, which may have caused measurement errors. Further studies on the causal relationship and not only the correlation between corneal nerves and epithelial thickening are needed in the future.

Conclusions

Our study provides new insights into the changes in CET and SNP profiles after SMILE for low-to-moderate myopia from a positional structural perspective. The postoperative CET and SNP profiles were uneven in different corneal areas and were positively correlated with each other, suggesting that non-uniform SNP regeneration may render the uneven CET changes.

Acknowledgments

The authors would like to thank all participants of the study.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-1887/rc

Funding: This study was funded by the Tianjin Science and Technology Bureau Project (No. 21JCZDJC01010) and the Tianjin Key Medical Discipline (Specialty) Construction Project (No. TJYXZDXK-037A).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1887/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the ethics committee of Tianjin Medical University Eye Hospital (approval No. 2023KY-10). All patients signed the informed consent form before being enrolled.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Reinstein DZ, Archer TJ, Vida RS. Epithelial thickness mapping for corneal refractive surgery. Curr Opin Ophthalmol 2022;33:258-68. [Crossref] [PubMed]
2. Zhou W, Reinstein DZ, Chen X, Chen S, Xu Y, Utheim TP, Stojanovic A. Transepithelial Topography-Guided Ablation Assisted by Epithelial Thickness Mapping for Treatment of Regression After Myopic Refractive Surgery. J Refract Surg 2019;35:525-33. [Crossref] [PubMed]
3. Hwang ES, Schallhorn JM, Randleman JB. Utility of regional epithelial thickness measurements in corneal evaluations. Surv Ophthalmol 2020;65:187-204. [Crossref] [PubMed]
4. Saleh S, Epp LJ, Manche EE. Effect of corneal epithelial remodeling on visual outcomes of topography-guided femtosecond LASIK. J Cataract Refract Surg 2022;48:1155-61. [Crossref] [PubMed]
5. Luft N, Ring MH, Dirisamer M, Mursch-Edlmayr AS, Kreutzer TC, Pretzl J, Bolz M, Priglinger SG. Corneal Epithelial Remodeling Induced by Small Incision Lenticule Extraction (SMILE). Invest Ophthalmol Vis Sci 2016;57:176-83. [Crossref] [PubMed]
6. Wu J, Xiong L, Zhang B, Chen B, Wang Z. Uneven Corneal Epithelial Redistribution After Femtosecond Laser-Assisted Lenticule Intrastromal Keratoplasty in Correcting Moderate-to-High Hyperopia. J Refract Surg 2024;40:e321-7. [Crossref] [PubMed]
7. Müller LJ, Marfurt CF, Kruse F, Tervo TM. Corneal nerves: structure, contents and function. Exp Eye Res 2003;76:521-42. [Crossref] [PubMed]
8. Feinberg K, Tajdaran K, Mirmoeini K, Daeschler SC, Henriquez MA, Stevens KE, Mulenga CM, Hussain A, Hamrah P, Ali A, Gordon T, Borschel GH. The Role of Sensory Innervation in Homeostatic and Injury-Induced Corneal Epithelial Renewal. Int J Mol Sci 2023;24:12615. [Crossref] [PubMed]
9. Liu C, Lin MT, Lee IXY, Mehta JS, Liu YC. Impact of corrected refractive power on the corneal denervation and ocular surface in small-incision lenticule extraction and LASIK. J Cataract Refract Surg 2023;49:1106-13. [Crossref] [PubMed]
10. Recchioni A, Sisó-Fuertes I, Hartwig A, Hamid A, Shortt AJ, Morris R, Vaswani S, Dermott J, Cerviño A, Wolffsohn JS, O'Donnell C. Short-Term Impact of FS-LASIK and SMILE on Dry Eye Metrics and Corneal Nerve Morphology. Cornea 2020;39:851-7. [Crossref] [PubMed]
11. Erie JC, McLaren JW, Hodge DO, Bourne WM. Recovery of corneal subbasal nerve density after PRK and LASIK. Am J Ophthalmol 2005;140:1059-64. [Crossref] [PubMed]
12. Li M, Liu L, Shi Y, Sun L, Ma X, Zou J. Age-related differences in corneal nerve regeneration after SMILE and the mechanism revealed by metabolomics. Exp Eye Res 2021;209:108665. [Crossref] [PubMed]
13. Song Y, Deng S, Lyv X, Xu Y, Zhang F, Guo N. Corneal subbasal nerve plexus reinnervation and stromal cell morphology with different cap thicknesses in small incision lenticule extraction. Eye Vis (Lond) 2024;11:15. [Crossref] [PubMed]
14. Yang LWY, Mehta JS, Liu YC. Corneal neuromediator profiles following laser refractive surgery. Neural Regen Res 2021;16:2177-83. [Crossref] [PubMed]
15. Chen X, Graham J, Dabbah MA, Petropoulos IN, Tavakoli M, Malik RA. An Automatic Tool for Quantification of Nerve Fibers in Corneal Confocal Microscopy Images. IEEE Trans Biomed Eng 2017;64:786-94. [Crossref] [PubMed]
16. Sekundo W, Kunert KS, Blum M. Small incision corneal refractive surgery using the small incision lenticule extraction (SMILE) procedure for the correction of myopia and myopic astigmatism: results of a 6 month prospective study. Br J Ophthalmol 2011;95:335-9. [Crossref] [PubMed]
17. Chin JY, Yang LWY, Ji AJS, Nubile M, Mastropasqua L, Allen JC, Mehta JS, Liu YC. Validation of the Use of Automated and Manual Quantitative Analysis of Corneal Nerve Plexus Following Refractive Surgery. Diagnostics (Basel) 2020.
18. Liu M, Jin C, Lu L, Yuan Y, Chen C, Zhao T, Ke B. The Impact of Corneal Epithelial Thickening and Inhomogeneity on Corneal Aberrations After Small Incision Lenticule Extraction. J Refract Surg 2023;39:23-32. [Crossref] [PubMed]
19. Kanellopoulos AJ. Comparison of Corneal Epithelial Remodeling Over 2 Years in LASIK Versus SMILE: A Contralateral Eye Study. Cornea 2019;38:290-6. [Crossref] [PubMed]
20. Zhu M, Xin Y, Vinciguerra R, Wang Z, Warsame AM, Wang C, Zhu D, Qu Z, Wang P, Zheng X, Wang J, Wang Q, Ye Y, Chen S, Bao F, Elsheikh A. Corneal Epithelial Remodeling in a 6-Month Follow-up Period in Myopic Corneal Refractive Surgeries. J Refract Surg 2023;39:187-96. [Crossref] [PubMed]
21. Romito N, Trinh L, Goemaere I, Borderie V, Laroche L, Bouheraoua N. Corneal Remodeling After Myopic SMILE: An Optical Coherence Tomography and In Vivo Confocal Microscopy Study. J Refract Surg 2020;36:597-605. [Crossref] [PubMed]
22. Ganesh S, Brar S, Relekar KJ. Epithelial Thickness Profile Changes Following Small Incision Refractive Lenticule Extraction (SMILE) for Myopia and Myopic Astigmatism. J Refract Surg 2016;32:473-82. [Crossref] [PubMed]
23. Ying J, Zhang J, Cai J, Pan F. Comparative Change in Anterior Corneal Asphericity After FS-LASIK and SMILE. J Refract Surg 2021;37:158-65. [Crossref] [PubMed]
24. Moshirfar M, Cha DS, Santos JM, Herron MS, Hoopes PC. Changes in Posterior Cornea and Posterior-To-Anterior Curvature Radii Ratio 1 Year After LASIK, PRK, and SMILE Treatment of Myopia. Cornea 2024;43:950-4. [Crossref] [PubMed]
25. Holladay JT, Dudeja DR, Chang J. Functional vision and corneal changes after laser in situ keratomileusis determined by contrast sensitivity, glare testing, and corneal topography. J Cataract Refract Surg 1999;25:663-9. [Crossref] [PubMed]
26. Hou J, Wang Y, Lei Y, Zheng X, Zhang Y. Corneal Epithelial Remodeling and Its Effect on Corneal Asphericity after Transepithelial Photorefractive Keratectomy for Myopia. J Ophthalmol 2016;2016:8582362. [Crossref] [PubMed]
27. Mohamed-Noriega K, Riau AK, Lwin NC, Chaurasia SS, Tan DT, Mehta JS. Early corneal nerve damage and recovery following small incision lenticule extraction (SMILE) and laser in situ keratomileusis (LASIK). Invest Ophthalmol Vis Sci 2014;55:1823-34. [Crossref] [PubMed]
28. Hou C, Li J, Li J, Peng H, Wang Q. In vivo confocal microscopy of sub-basal corneal nerves and corneal densitometry after three kinds of refractive procedures for high myopia. Int Ophthalmol 2023;43:925-35. [Crossref] [PubMed]
29. Kowtharapu BS, Stachs O. Corneal Cells: Fine-tuning Nerve Regeneration. Curr Eye Res 2020;45:291-302. [Crossref] [PubMed]
30. Wilson SE. Laser in situ keratomileusis-induced (presumed) neurotrophic epitheliopathy. Ophthalmology 2001;108:1082-7. [Crossref] [PubMed]
31. Lambiase A, Manni L, Bonini S, Rama P, Micera A, Aloe L. Nerve growth factor promotes corneal healing: structural, biochemical, and molecular analyses of rat and human corneas. Invest Ophthalmol Vis Sci 2000;41:1063-9.
32. Chin JY, Lin MT, Lee IXY, Mehta JS, Liu YC. Tear Neuromediator and Corneal Denervation Following SMILE. J Refract Surg 2021;37:516-23. [Crossref] [PubMed]