
==== Front
Sci Rep
Sci Rep
Scientific Reports
2045-2322
Nature Publishing Group UK London

71604
10.1038/s41598-024-71604-y
Article
Analysis of corneal remodeling post-myopic photorefractive keratectomy with the WaveLight® EX500 excimer laser
Memmi Benjamin 1
Knoeri Juliette 1
Leveziel Loïc 1
Georgeon Cristina 1
Bouheraoua Nacim 1
Borderie Vincent vincent.borderie@upmc.fr

12
1 grid.462844.8 0000 0001 2308 1657 Groupe de Recherche Clinique #32, Transplantation Et Thérapies Innovantes de La Cornée, Sorbonne Université, Hôpital National des 15-20, Paris, France
2 https://ror.org/024v1ns19 grid.415610.7 0000 0001 0657 9752 Service d’ophtalmologie 5, Hôpital National des 15-20, 28 Rue de Charenton, 75012 Paris, France
7 9 2024
7 9 2024
2024
14 208881 2 2024
29 8 2024
© The Author(s) 2024
2024
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Refractive error is becoming a significant public health issue. Photorefractive Keratectomy (PRK) is a corneal surface surgical technique that removes the corneal epithelium before stromal photoablation by ultraviolet radiation from the Excimer laser. We designed a retrospective study to characterize corneal remodeling after myopic Photorefractive Keratectomy and assess the accuracy of laser-predicted ablation depth (AD). This study took place in 15–20 National Ophthalmology Hospital, Paris, France. 150 eyes with preoperative manifest spherical equivalent between − 10.00D and − 0.25D and cylinder < 3D, treated with the WaveLight® EX500 laser between 01/2019 and 01/2023, were followed for at least three months. The main outcome measurements were postoperative changes in epithelial (ET) and stromal (ST) thicknesses measured with spectral domain optical coherence tomography and mean simulated keratometry (SimK) assessed with corneal topography. The central ET significantly decreased at M1, increased over the preoperative value from M1 to M6, and stabilized after M6. The increase in central ET after M1 was associated with an increase in mean SimK (r = 0.34). The achieved AD was 7.9 ± 8.0 µm greater than the laser-predicted AD. Stromal over-ablation was significantly and independently associated with myopia > 6D preoperative mean SimK > 44D and transepithelial procedures.

Subject terms

Corneal diseases
Refractive errors
Agence Nationale de la RechercheANR-21-CE19-0010-02 ANR-21-CE19-0010-02 ANR-21-CE19-0010-02 ANR-21-CE19-0010-02 Memmi Benjamin Knoeri Juliette Bouheraoua Nacim Borderie Vincent issue-copyright-statement© Springer Nature Limited 2024
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pmcIntroduction

Refractive error is a leading cause of reversible visual impairment1. The incidence of myopia is currently increasing worldwide2. It is becoming a significant public health issue, with billions of people (i.e., 49.8% of the world population) estimated to be affected by this condition by 20503. The effect of refractive surgery on patients extends beyond spectacle independence, with the procedure leading to improved quality of life, better working ability, and improved daily working performance4. Photorefractive Keratectomy (PRK) was developed four decades ago and improved with time5. It is a corneal surface surgical technique that removes the corneal epithelium before stromal photoablation by ultraviolet radiation from the Excimer laser (an acronym for Excited Dimer). It has been established as a reasonably safe procedure producing excellent visual outcomes6,7. The WaveLight® EX500 excimer laser (Alcon Laboratories®, Fort Worth, TX, USA) is a well-known platform for refractive surgery8. This platform proposes an estimation of the residual stroma after treatment9. Post-treatment residual stromal bed (RSB) thickness is associated with the risk of postoperative corneal ectasia10,11. While wound healing after PRK has been well characterized12, very little data are available concerning its implications on keratometry and spherical equivalents. The WaveLight® EX500 estimation of residual stroma after treatment has never been evaluated after PRK11,13.

This study aims to describe the natural corneal remodeling after myopic treatment and its consequences on refraction. It also compares the OCT measurement of the RSB after myopic treatment with the pre-treatment estimation provided by the WaveLight® EX500 laser.

Material and methods

Study design

This retrospective study was conducted between January 1, 2019, and January 1, 2023. The study adhered to the tenets of the Declaration of Helsinki and was approved by the Ethics Committee of the French Society of Ophthalmology (IRB #00008855). Informed consent was obtained from all participants or their legal guardians.

Inclusion criteria were the following: myopic photorefractive keratectomy (PRK) performed by one surgeon (V.B) with the WaveLight® EX500 (Alcon Laboratories®, Fort Worth, TX, USA) platform, with the wavefront-optimized module in a tertiary institution (Hôpital National des 15–20, Paris, France), preoperative manifest refractive spherical equivalent < 0D, preoperative manifest refractive cylinder < 3D, available spectral domain optical coherence tomography (SD-OCT) data, available corneal topography data, postoperative follow-up of at least three months. Exclusion criteria include presbyopic patients, patients with corneal scars, and patients with severe dry eye or systemic disease. Two hundred fifty-six eyes underwent PRK from January 2019 to January 2023, of which 150 were included in this study.

The primary outcome measurements were the postoperative changes in epithelial and stromal thicknesses measured with spectral domain optical coherence tomography (SD-OCT) and in mean keratometry of the anterior corneal surface measured with corneal topography. As the maximum AD is located in the central part of the cornea in myopic PRK procedures, we used the central epithelial and stroma thicknesses as target measurements.

Surgical procedures and patient follow-up

Manifest refraction was used for laser programming. We applied the nomogram provided by the laser manufacturer (Table 1).Table 1 Nomogram provided by the laser manufacturer to determine the correction to apply to the manifest refractive spherical equivalent.

Manifest spherical equivalent	Programmed SE	
 >  − 2.5D*	augmented by 0.25D	
 − 2.50D to − 5.25D	not modified	
 − 5.50D to − 7.00D	decreased by 0.25D	
 − 7.25D to − 8.25D	decreased by 0.50D	
 − 8.50D to − 9.50D	decreased by 0.75D	
 − 9.75D and − 10.50D	decreased by 1.00D	
This nomogram anticipates an overcorrection for higher correction.

*D stands for diopters.

p values in bold indicate significance (p < 0.05).

The target postoperative refraction was 0 D with an RSB thickness of at least 400 µm.

Patients were operated under topical anesthesia (lidocaine gel). The ocular surface and eyelids were decontaminated twice with povidone-iodine. The corneal epithelium was removed with the excimer laser (transepithelial PRK, StreamLight), mechanical debridement, or alcohol debridement. Regarding transepithelial PRK, epithelium removal was customized according to the patient's maximal epithelial thickness in the 6-mm central zone. The maximum epithelial thickness measured in the SD-OCT 6-mm epithelial map was used for the laser epithelial ablation depth. The ocular surface was rinsed with a balanced salt solution (BSS) and dried before laser treatment, followed by BSS irrigation to decrease corneal temperature. Eyes with more than two diopters spherical equivalent received 0.2 mg/ml mitomycin application with a soaked sponge for 20 s, followed by BSS irrigation. A bandage contact lens was used systematically and was removed on postoperative day 3. If the epithelium was not completely healed by day 3, Vitamin A ointment was applied for the next three days. No additional bandage contact lens was used during this period. Postoperative treatment included ofloxacin for one week, dexamethasone eyedrops three times a day for one month, and artificial tears for three months.

Patients were assessed before surgery, at one month, three months, six months, and after that with SD-OCT and corneal topography. Uncorrected and best spectacle-corrected visual acuity and slit-lamp findings were recorded at each examination.

Data collection

Clinical features (i.e., patient age, uncorrected and best spectacle-corrected visual acuity, manifest refraction, slit-lamp findings), surgical data (i.e., PRK technique, mitomycin application, programmed correction, optical zone, treatment diameter, laser-predicted maximal ablation depth), SD-OCT, and corneal topography were recorded. A 12-mm spectacle distance was used to convert refractive data from the spectacle plane to the corneal plane.

Spectral domain-optical coherence tomography

We acquired 6 mm-wide SD-OCT scans (Optovue RTVue-100®; Optovue Inc®, Fremont, California, USA) with the long corneal adaptor module (CAM-L) in the center of the cornea. This device includes epithelial mapping software. Scans had an axial resolution of 5 μm and a transverse resolution of 15 μm. Corneal, epithelial, and stromal data within the 6-mm zone were recorded for each eye. Epithelial mapping is divided into three areas: Central Epithelial Thickness (CET, 0 to 2 mm), ParaCentral Epithelial Thickness (PCET, 2 to 5 mm), and MidPeripheral Epithelial Thickness (MPET, 5 to 6 mm).

Corneal topography

Corneal topography was assessed with the MS39® topographer (CSO, Firenze, Italy). This device combines Placido Disc topography with Spectral-Domain anterior segment OCT for detailed corneal analysis. We recorded the following topographic indices from the anterior sagittal map: mean simulated keratometry (Mean K), simulated keratometry of the flat (Kflat) and steep (Ksteep) meridians.

Statistical analysis

The R-Studio software® was used to perform statistical analysis. Changes in quantitative variables between two timeframes were assessed with the paired t-test. Comparison of groups was performed with the unpaired t-test and analysis of variance. Regression analysis was performed using the Pearson correlation coefficient and multiple linear regression.

Results

Study population and overall outcomes

150 eyes of 86 patients with myopic PRK were included in this study. Patient and surgical characteristics are summarized in Table 2. No intraoperative complications were recorded. The average preoperative refractive spherical equivalent was − 3.50 ± 2.00 D (− 10.00; − 0.25). This figure increased by + 3.41 ± 1.92 D (− 0.75; + 9.25) on average from the preoperative assessment to the last examination. The mean simulated keratometry decreased by 2.91 ± 1.49 D (− 0.2; − 7.8) on average. The mean laser-predicted ablation depth was 54.2 ± 22.9 µm (16;118). The stromal thickness decreased by 61.5 ± 26.3 µm (− 135; − 9), and the epithelial thickness increased by 2.7 ± 5.1 µm (− 14; + 15) on average. Stromal haze was observed in 2 eyes (1.3%) of 1 patient with no decrease in visual acuity and disappeared during follow-up. No other postoperative complications were recorded.Table 2 Characteristics of 150 myopic photorefractive keratectomies (PRK).

	Mean ± standard deviation or number (percentage)	Range	
Age (years)	32.9 ± 6.9	[23;61]	
Sexe ratio	1:1		
Right Eye / Left Eye	81:69		
Follow-up (months)	7.1 ± 5.6	[3;33]	
 Number of eyes assessed at three months	150 (100%)		
 Number of eyes assessed at six months	86 (57.3%)		
 Number of eyes assessed after six months	52 (34.7%)		
Surgical procedure	
 Ablation depth (microns)	 − 54.2 ± 22.9	[− 118; − 16]	
 Optical zone (mm)	6.5		
 Treatment diameter (mm)	8.5 ± 0.9	[6.5;9.0]	
 Alcohol epithelial debridement	102 (68.0%)		
 Laser epithelial debridement (transepithelial PRK)	34 (22.7%)		
 Mechanical epithelial debridement	14 (9.3%)		
 Mitomycin application	87 (58.0%)		
Spherical Equivalent (SE, Diopters)	
 Pre-operative SE	 − 3.50 ± 2.00	[− 10.00; − 0.25]	
 Post-operative SE at the last follow-up	 − 0.09 ± 0.56	[− 1.50; + 1.25]	
 Change from the preoperative value	 + 3.41 ± 1.92	[− 0.75; + 9.25]	
Uncorrected Visual Acuity (UCVA, LogMAR)	
 Pre-operative UCVA

  − 20/25 or better

  − 20/40 or better

	0.95 ± 0.44

3 (2.0%)

15 (10.0%)

	[0.05;1.70]	
Post-operative UCVA at the last follow-up

  − 20/25 or better

  − 20/40 or better

	 − 0.02 ± 0.11

142 (94.7%)

146 (97.3%)

	[− 0.20;0.60]	
Best Corrected Visual Acuity (BCVA, LogMAR)	
 Pre-operative BCVA

  − 20/25 or better

  − 20/40 or better

	 − 0.01 ± 0.04

149 (99.3%)

150 (100.0%)

	[− 0.10;0.10]	
Post-operative BCVA at the last follow-up

  − 20/25 or better

  − 20/40 or better

	 − 0.04 ± 0.06

149 (99.3%)

150 (100.0%)

	[− 0.20;0.15]	
Central Corneal Thickness (CCT, microns)	
 Pre-operative CCT	544.8 ± 33.2	[485;629]	
 Post-operative CCT at the last follow-up	485.9 ± 36.9	[417;582]	
 Change from the preop value	 − 58.9 ± 25.4	[− 131; − 10]	
Central Epithelial Thickness (CET, microns)	
 Pre-operative CET	53.4 ± 3.3	[46;63]	
 Post-operative CET at the last follow-up	56.1 ± 5.1	[41;71]	
 Change from the preop value	 + 2.7 ± 5.1	[− 14; + 15]	
ParaCentral Epithelial Thickness (PCET, microns)	
 Pre-operative PCET	53.7 ± 3.1	[45;63]	
 Post-operative PCET at the last follow-up	56.8 ± 4.7	[43;70]	
 Change from the preop value	 + 3.4 ± 4.2	[− 10; + 18]	
MidPeripheral Epithelial Thickness (MPET, microns)	
 Pre-operative MPET	53.8 ± 3.1	[44;63]	
 Post-operative MPET at the last follow-up	54.9 ± 3.7	[47;65]	
 Change from the preop value	 + 1.4 ± 3.1	[− 7;12]	
Central Stromal Thickness (CST, microns)	
 Pre-operative CST	491.4 ± 32.7	[430;571]	
 Post-operative CST at the last follow-up	429.9 ± 36.9	[362;516]	
Change from the preop value	 − 61.5 ± 26.3	[− 135; − 9]	
Mean Simulated Keratometry (Diopters)	
 Pre-operative	43.77 ± 1.46	[40.5;47.5]	
 Post-operative	40.86 ± 2.05	[35.0;45.4]	
 Change from the preop value	 − 2.91 ± 1.49	[− 0.2; − 7.8]	

Corneal epithelial and stromal remodeling after myopic PRK (Table 3)

Table 3 Changes in Corneal Thickness and Keratometry at Various Postoperative Time Points Following Myopic Photorefractive Keratectomy (PRK).

Period	Change in Central Epithelial Thickness (µm)*	Change in Central Stromal Thickness (µm)*	Change in Central Corneal Thickness (µm)*	Change in Mean Simulated Keratometry (D)**	
Preop to M1 (n = 150)	 − 4.7 ± 5.1 (p < 0.000001)	 − 65.0 ± 28.4 (p < 0.000001)	 − 69.7 ± 29.2 (p < 0.000001)	3.0 ± 1.7 (p < 0.000001)	
M1 to M3 (n = 150)	 + 6.3 ± 4.3 (p < 0.000001)	 + 3.9 ± 2.0 (p = 0.05)	 + 9.3 ± 9.9 (p < 0.000001)	 + 0.1 ± 0.4 (p = 0.09)	
M3 to M6 (n = 86)	 + 2.3 ± 3.3 (p = 0.0004)	 + 1.5 ± 5.7 (p = 0.13)	 + 3.8 ± 2.9 (p = 0.006)	 + 0.1 ± 0.2 (p = 0.004)	
M6 to Last Examination (n = 52)	 + 1.4 ± 3.8 (p = 0.21)	 + 0.8 ± 5.4 (p = 0.58)	 + 2.2 ± 5.1 (p = 0.14)	 + 0.0 ± 0.2 (p = 0.84)	
*µm = microns.

**D = diopters.

The central epithelial thickness (CET) significantly decreased by 4.7 ± 5.1 µm (p < 0.00001) from preoperative assessment to 1 month postoperatively. This figure increased by 6.3 ± 4.3 µm (p < 0.00001) from M1 to M3 and 2.3 ± 3.3 µm (p = 0.0004) from M3 to M6. It remained stable between M6 and the last examination (Fig. 1A). The central stromal thickness (ST) significantly decreased by 65.0 ± 28.4 µm (p < 0.00001) from preoperative assessment to M1. This figure then remained stable after M1 (Fig. 1B). The central corneal thickness significantly decreased by 69.5 ± 29.2 µm (p < 0.00001) from preoperative assessment to 1 month postoperatively. This figure increased by 9.3 + 9.9 µm from M1 to M3 and 3.8 + 2.9 µm (p < 0.00001) from M3 to M6 and remained stable between M6 and the last examination. Figure 2 reproduces Fig. 1, separating the methods of epithelial removal to ensure that the trends are similar for the different types of procedure.Fig. 1 Epithelial (A) and stromal (B) remodeling after myopic PRK from pre-operative to six months.

Fig. 2 Epithelial (A) and stromal (B) remodelling after myopic PRK, from the pre-operative period to six months, according to PRK (1) or TransPRK (2).

Relationships between epithelial/stromal remodeling and changes in keratometry

The decrease in central ST between preoperative assessment and M1 was significantly associated with a decrease in mean SimK (r = 0.87; p < 0.00001). Conversely, the change in CET between preoperative assessment and M1 did not significantly correlate with the change in mean SimK (r = − 0.13, p = 0.16). The increase in CET between M1 and the last examination was significantly associated with an increase in mean SimK (r = 0.34; p = 0.0001). More precisely, we calculated the Epithelial Delta (MPET—CET) at M1 and last examination, and the variation in this Epithelial Delta was strongly correlated with the keratometric increase (r = 0.40; p < 0.0001) (Fig. 3). On average, a 1-µm increase in central ET was associated with a 0.03D increase in mean SimK. Conversely, the change in central ST between M1 and the last examination did not significantly correlate with the change in mean SimK (r = − 0.12, p = 0.19). From the preoperative assessment to the last examination, the decrease in central ST (r = 0.87; p < 0.00001) and central CT (r = 0.87; p < 0.00001) and the increase in central ET (r = − 0.19, p = 0.02) were significantly associated with, respectively, a decrease and an increase in mean SimK.Fig. 3 Correlation between changes in Epithelial Delta and changes in mean simulated keratometry. Postoperative central epithelial thickening is associated with regression of the laser refractive effect.

Difference between the theoretical and achieved stromal ablation depths

Several sub-groups were created for this analysis: patients were separated according to their average keratometry (greater or less than 44 diopters) and their myopia spherical equivalent (less than three diopters, between 3 and 6 diopters, and more than six diopters). Results are described in Table 4.Table 4 Differences Between OCT measured and Laser Estimation of Maximum Stromal Ablation Depth.

	Difference between Laser Estimated and OCT-measured Ablation Depths (microns)		
	Groups	Minimum	Median	Maximum	Mean (95% Confidence Interval)	Comparison of mean to 0	Multiple linear regression	
	All eyes (n = 150)	 − 31.00	 − 8.41	12.00	 − 7.90 (− 9.2 to − 6.6)	p < 0.001		
Keratometry	 < or = 44D (n = 89)	 − 28.00	 − 8.00	12.00	 − 6.55 (− 8.1 to − 5.0)	p < 0.001	p = 0.02	
 > 44D (n = 61)	 − 31.00	 − 9.03	10.00	 − 9.90 (− 12.2 to − 7.6)	p < 0.001	
Mitomycin C	Yes (n = 87)	 − 29.00	 − 9.00	12.00	 − 8.50 (− 10.2 to − 6.7)	p < 0.001	p = 0.98	
No (n = 63)	 − 31.00	 − 6.92	5.40	 − 7.09 (− 9.08 to − 5.10)	p < 0.001	
Surgical procedure	Standard PRK (n = 116)	 − 31.00	 − 7.155	12.00	 − 7.10 (− 8.62 to − 5.57)	p < 0.001	p = 0.02	
Transepithelial PRK (n = 34)	 − 24.00	 − 10.68	2.90	 − 10.68 (− 12.95 to − 8.40)	p < 0.001	
SE	 < 3D (n = 70)	 − 31.00	 − 5.53	12.00	 − 5.49 (− 7.40 to − 3.59)	p < 0.001	p = 0.001	
 > 3D and < 6D (n = 64)	 − 26.00	 − 9.00	10.00	 − 8.78 (− 10.51 to − 7.05)	p < 0.001	
 > 6D (n = 16)	 − 28.00	 − 13.89	3.00	 − 13.42 (− 17.63 to − 9.22)	p < 0.001	
p values in bold indicate significance (p < 0.05).

At the last examination, the achieved AD was, on average, 7.9 ± 8.0 µm greater than the laser theoretical AD (p < 0.000001, Fig. 4A). The difference between the achieved and theoretical ADs significantly correlated with the spherical equivalent (p = 0.001, Fig. 4B). The higher the myopia, the more the laser platform underestimates the actual ablation (Fig. 5A). We performed adjusted multiple linear regression, which found a significant independent correlation for keratometry, surgical procedure, and spherical equivalent (Table 4). Patients with average keratometry greater than 44D had a significantly higher difference in stromal ablation depth between laser estimation and OCT measurement (p = 0.02, Fig. 5B), as did patients who underwent transepithelial PRK (p = 0.02). Conversely, mitomycin C use and pre-operative stromal thickness were not associated with stromal over-ablation.Fig. 4 (A) Graphic density representation of stromal ablation depth difference between preoperative laser platform estimation and OCT measurements. (B) Comparison of stromal ablation depth between preoperative laser estimation and OCT measurements.

Fig. 5 Graphic representation of stromal ablation depth difference between preoperative laser platform estimation and OCT measurements according to myopia (A), keratometry (B) and procedure (C).

Discussion

Analysis of corneal response to laser treatment reveals epithelial thinning during the postoperative first month, followed by central epithelial thickening, which is high between M1 and M3 and low between M3 and M6. Similar to the findings of Sedaghat et al.,14 we observed that central thickening was greater than peripheral thickening and was associated with a modest regression of the mean simulated keratometry. In contrast, De Ortueta et al.15 described epithelial thickening as diffuse, without any specific pattern. The study focused on eyes treated exclusively with transepithelial PRK for moderate myopia and included a follow-up period of only four months, which might explain the differences observed compared to our results. The epithelial thickness appears to stabilize after M6. However, the number of eyes followed for more than six months (i.e., 52 out of 150) could be too low to detect a low change in ET after M616. These results are consistent with those reported in the literature12,13,17. The stroma does not appear to undergo clinically relevant changes in thickness after M1. Our study is the largest cohort describing epithelial and stromal thickness profiles after PRK. In 2015, Chen et al. published a retrospective study of 46 myopic eyes treated with PRK and observed similar results18. They did not find the postoperative epithelial thickening to affect the refractive outcomes as we did. However, the number of eyes included was lower in their study, and our study's regression effect associated with epithelial thickening was statistically significant, although weak.

The safety of the laser procedure results from several factors, including the RSB thickness after treatment. A low RSB thickness is associated with a higher risk of postoperative corneal ectasia10. Before surgery, the expected residual minimal stromal thickness is calculated based on the minimal (central for myopic treatment) corneal thickness, the central thickness of the epithelium (for PRK) or flap (for LASIK), and the theoretical AD. As demonstrated in the present study, underestimating the theoretical AD may result in a too-thin RSB. In our series, the achieved AD was significantly higher (on average, 7.9 ± 8.0) than the laser-predicted AD. We aimed to keep an RSB of at least 400 µm to preserve corneal biomechanical properties. However, the minimal RSB thickness necessary to prevent postoperative ectasia after PRK is challenging to determine as post-PRK ectasia is mainly related to pre-existing forme fruste keratoconus19. This underestimation of the stromal AD is a concern that could lead to further corneal ectasia, mainly if this is applied to LASIK, where the stromal ablation is deeper compared with PRK. Febbraro et al.20 have previously described underestimation of stromal AD, but only for high myopia. However, 89 eyes were included in this study, and pachymetry measurements were achieved with the Pentacam (Scheimpflug pachymetry measurements). To approach the actual AD, the laser-predicted AD without implementing the nomogram can be checked, and it has been described to reduce the difference between laser-estimated and measured AD21. Steep cornea over 44D, high myopia, and transepithelial procedure were independent risk factors for under-estimated AD. Notably, no prior study has highlighted a steep cornea as a risk factor. Our findings align with the work of Christiansen et al., who demonstrated that eyes with steeper corneas preoperatively have inferior visual outcomes following myopic LASIK22. The transepithelial procedure includes a full-thickness epithelial photoablation23. Although the epithelium removal has been customized to the patient, it is possible that some transepithelial procedures have removed part of the stroma and explain this result. Ablation depth increased with higher myopic correction, supposing that the same laser spot may not have the same ablation effect just beneath Bowman’s layer and deeper in the anterior or mid-stroma. Keratocyte density and stromal lamellae organization could explain this finding. Keratocyte density decreases with stromal depth, with the very anterior stroma beneath Bowman’s layer featuring a very high density24. The packing density of stromal lamellae is higher in the anterior than in the posterior stroma, and anterior lamellae are highly interwoven, and most insert into Bowman's layer25.

A few studies have already demonstrated the importance of corneal biomechanics, which could explain the variability of the stromal response to the excimer laser. Myopic LASIK produces different degrees of central flattening and postoperative ametropia in low-stiffness and high-stiffness corneas in whole-eye finite element analysis26. Recently, the postoperative residual refractive error after small-incision lenticule extraction has been shown to be associated with preoperative corneal stiffness27. In PRK procedures, corneal stiffness could influence the ablation effect of the laser spot (i.e., AD could be lower for stiff corneas).

This study is subject to several limitations. First, the retrospective design of our study and the variability in follow-up durations present a challenge in evaluating the longitudinal effects of PRK surgery consistently across all subjects. This disparity in follow-up periods could influence the comparability of our findings. Another significant limitation stems from the various epithelial removal techniques, including mechanical, alcohol-assisted, and transepithelial PRK. Each method could potentially affect the healing dynamics and measurement outcomes differently, introducing variability into our study. Moreover, the selective application of mitomycin C only in eyes with more than two diopters spherical equivalent complicates the uniformity of postoperative recovery and results, possibly affecting epithelial regeneration and haze formation. Our study also contends with the inherent challenges of accurately measuring epithelial and stromal thickness following PRK surgery. The lack of a true Bowman's layer and the presence of variable degrees of corneal haze postoperatively are potential sources of measurement error. The changes in epithelial and stromal thicknesses observed in our study exceed the variability of the SD-OCT technology (i.e., 1 µm for epithelium and 2 µm for stroma)28. Changes in the posterior corneal interface are still challenging even if tomographic devices, such as the MS39® we used in the present study to measure corneal topography, provide posterior corneal curvature measurements. To improve the safety and accuracy of the laser procedure, better knowledge of the factors influencing the laser effect is needed. The location of the laser spot in the stromal depth and corneal curvature could be used in algorithms to predict the therapeutic effect (i.e., the change in corneal refractive power) and safety parameters, including RSB. Artificial intelligence-based algorithms developed with local data for a given laser could be more efficient than the algorithm provided by the laser manufacturer. Another way to improve safety and accuracy is to control the ablation depth during the laser procedure. Real-time optical coherence tomography technologies, such as those used in intraoperative OCT devices, could provide feedback to the laser so that the treatment is stopped when the intended ablation depth is reached. Our study provides new insight to understand the response variability after PRK treatment.

Conclusion

Myopic photorefractive keratectomy is a safe surgery that gives excellent refractive results overall. Whereas the epithelium thickens and explains treatment regression, the stroma remains stable after the first postoperative month. The AD is underestimated by the WaveLight® EX500 platform, especially in important myopic treatment, transepithelial procedure, and steep cornea. To approach a perfect and reproducible result, the future lies in searching for personalized treatment adapted to each cornea, according to cornea curvature and biomechanics.

Author contributions

Contributions of authors: design of the study (B.M., V.B.); conduct of the study (B.M., J.K., L.L., C.G., N.B., V.B.); collection, management, analysis, and interpretation of data (B.M., C.G., J.K., N.B., V.B.); preparation, review, and approval of manuscript (B.M., J.K., L.L., N.B., V.B.).

Data availability

The datasets analysed during the current study are available from the corresponding author on reasonable request.

Competing interests

The authors declare no competing interests.

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References:

1. Global causes of blindness and distance vision impairment 1990–2020: a systematic review and meta-analysis - The Lancet Global Health. https://www.thelancet.com/journals/langlo/article/PIIS2214-109X(17)30393-5/fulltext.
2. Shinojima A Negishi K Tsubota K Kurihara T Multiple factors causing myopia and the possible treatments: A mini review Front. Public Health 2022 10.3389/fpubh.2022.897600 35619815
Shinojima, A., Negishi, K., Tsubota, K. & Kurihara, T. Multiple factors causing myopia and the possible treatments: A mini review. Front. Public Health10.3389/fpubh.2022.897600 (2022).35619815 10.3389/fpubh.2022.897600
3. Holden BA Global prevalence of myopia and high myopia and temporal trends from 2000 through 2050 Ophthalmology 2016 123 1036 1042 10.1016/j.ophtha.2016.01.006 26875007
Holden, B. A. et al. Global prevalence of myopia and high myopia and temporal trends from 2000 through 2050. Ophthalmology 123, 1036–1042 (2016).26875007 10.1016/j.ophtha.2016.01.006
4. Sugar A Hood CT Mian SI Patient-reported outcomes following LASIK: Quality of life in the PROWL studies JAMA 2017 317 204 205 10.1001/jama.2016.19323 28097345
Sugar, A., Hood, C. T. & Mian, S. I. Patient-reported outcomes following LASIK: Quality of life in the PROWL studies. JAMA 317, 204–205 (2017).28097345 10.1001/jama.2016.19323
5. Trokel SL Srinivasan R Braren B Excimer laser surgery of the cornea Am. J. Ophthalmol. 1983 96 710 715 10.1016/S0002-9394(14)71911-7 6660257
Trokel, S. L., Srinivasan, R. & Braren, B. Excimer laser surgery of the cornea. Am. J. Ophthalmol. 96, 710–715 (1983).6660257 10.1016/S0002-9394(14)71911-7
6. Hersh PS Results of phase III excimer laser photorefractive keratectomy for myopia Ophthalmology 1997 104 1535 1553 10.1016/S0161-6420(97)30073-6 9331190
Hersh, P. S. et al. Results of phase III excimer laser photorefractive keratectomy for myopia. Ophthalmology 104, 1535–1553 (1997).9331190 10.1016/S0161-6420(97)30073-6
7. Wen D postoperative efficacy, predictability, safety, and visual quality of laser corneal refractive surgery: A network meta-analysis Am. J. Ophthalmol. 2017 178 65 78 10.1016/j.ajo.2017.03.013 28336402
Wen, D. et al. postoperative efficacy, predictability, safety, and visual quality of laser corneal refractive surgery: A network meta-analysis. Am. J. Ophthalmol. 178, 65–78 (2017).28336402 10.1016/j.ajo.2017.03.013
8. Mifflin MD Betts BS Nguyen J Pouly S High myopic photorefractive keratectomy outcomes with the Alcon Wavelight® EX500 excimer laser Clin. Ophthalmol. 2018 12 1041 1048 10.2147/OPTH.S164110 29922033
Mifflin, M. D., Betts, B. S., Nguyen, J. & Pouly, S. High myopic photorefractive keratectomy outcomes with the Alcon Wavelight® EX500 excimer laser. Clin. Ophthalmol. 12, 1041–1048 (2018).29922033 10.2147/OPTH.S164110
9. Mifflin MD Mortensen XM Betts BS Gross C Zaugg B Accuracy of Alcon WaveLight® EX500 optical pachymetry during LASIK Clin. Ophthalmol. 2017 11 1513 1517 10.2147/OPTH.S138459 28860701
Mifflin, M. D., Mortensen, X. M., Betts, B. S., Gross, C. & Zaugg, B. Accuracy of Alcon WaveLight® EX500 optical pachymetry during LASIK. Clin. Ophthalmol. 11, 1513–1517 (2017).28860701 10.2147/OPTH.S138459
10. Randleman JB Russell B Ward MA Thompson KP Stulting RD Risk factors and prognosis for corneal ectasia after LASIK Ophthalmology 2003 110 267 275 10.1016/S0161-6420(02)01727-X 12578766
Randleman, J. B., Russell, B., Ward, M. A., Thompson, K. P. & Stulting, R. D. Risk factors and prognosis for corneal ectasia after LASIK. Ophthalmology 110, 267–275 (2003).12578766 10.1016/S0161-6420(02)01727-X
11. Randleman BJ Caster AI Banning CS Stulting DR Corneal ectasia after photorefractive keratectomy J. Cataract Refract. Surg. 2006 32 1395 10.1016/j.jcrs.2006.02.078 16863983
Randleman, B. J., Caster, A. I., Banning, C. S. & Stulting, D. R. Corneal ectasia after photorefractive keratectomy. J. Cataract Refract. Surg. 32, 1395 (2006).16863983 10.1016/j.jcrs.2006.02.078
12. Fagerholm P Wound healing after photorefractive keratectomy J. Cataract Refract. Surg. 2000 26 432 10.1016/S0886-3350(99)00436-8 10713242
Fagerholm, P. Wound healing after photorefractive keratectomy. J. Cataract Refract. Surg. 26, 432 (2000).10713242 10.1016/S0886-3350(99)00436-8
13. Wilson SE Biology of keratorefractive surgery- PRK, PTK, LASIK, SMILE, inlays and other refractive procedures Exp. Eye Res. 2020 198 108136 10.1016/j.exer.2020.108136 32653492
Wilson, S. E. Biology of keratorefractive surgery- PRK, PTK, LASIK, SMILE, inlays and other refractive procedures. Exp. Eye Res. 198, 108136 (2020).32653492 10.1016/j.exer.2020.108136
14. Sedaghat M-R Corneal epithelial thickness mapping after photorefractive keratectomy for myopia J. Refract. Surg. 2019 35 632 641 10.3928/1081597X-20190826-03 31610004
Sedaghat, M.-R. et al. Corneal epithelial thickness mapping after photorefractive keratectomy for myopia. J. Refract. Surg. 35, 632–641 (2019).31610004 10.3928/1081597X-20190826-03
15. de Ortueta D von Rüden D Arba-Mosquera S Refractive effect of epithelial remodelling in myopia after transepithelial photorefractive keratectomy Vision (Basel) 2022 6 74 10.3390/vision6040074 36548936
de Ortueta, D., von Rüden, D. & Arba-Mosquera, S. Refractive effect of epithelial remodelling in myopia after transepithelial photorefractive keratectomy. Vision (Basel) 6, 74 (2022).36548936 10.3390/vision6040074
16. Moshirfar M Mechanisms of optical regression following corneal laser refractive surgery: Epithelial and stromal responses Med. Hypothesis Discov. Innov. Ophthalmol 2018 7 1 9 29644238
Moshirfar, M. et al. Mechanisms of optical regression following corneal laser refractive surgery: Epithelial and stromal responses. Med. Hypothesis Discov. Innov. Ophthalmol 7, 1–9 (2018).29644238
17. Shetty R Early corneal and epithelial remodeling differences identified by OCT imaging and artificial intelligence between two transepithelial PRK platforms J. Refract. Surg. 2020 36 678 686 10.3928/1081597X-20200730-03 33034360
Shetty, R. et al. Early corneal and epithelial remodeling differences identified by OCT imaging and artificial intelligence between two transepithelial PRK platforms. J. Refract. Surg. 36, 678–686 (2020).33034360 10.3928/1081597X-20200730-03
18. Chen X postoperative changes in corneal epithelial and stromal thickness profiles after photorefractive keratectomy in treatment of myopia J. Refract. Surg. 2015 31 446 453 10.3928/1081597X-20150623-02 26186563
Chen, X. et al. postoperative changes in corneal epithelial and stromal thickness profiles after photorefractive keratectomy in treatment of myopia. J. Refract. Surg. 31, 446–453 (2015).26186563 10.3928/1081597X-20150623-02
19. Leccisotti A Corneal ectasia after photorefractive keratectomy Graefe’s Arch Clin. Exp. Ophthalmol. 2007 245 869 875 10.1007/s00417-006-0507-z 17177035
Leccisotti, A. Corneal ectasia after photorefractive keratectomy. Graefe’s Arch Clin. Exp. Ophthalmol. 245, 869–875 (2007).17177035 10.1007/s00417-006-0507-z
20. Febbraro J-L Comparison of laser platform estimation and objective measurement of maximum ablation depth using scheimpflug pachymetry in myopic femtosecond laser in situ keratomileusis Cornea 2020 39 316 320 10.1097/ICO.0000000000002143 31517724
Febbraro, J.-L. et al. Comparison of laser platform estimation and objective measurement of maximum ablation depth using scheimpflug pachymetry in myopic femtosecond laser in situ keratomileusis. Cornea 39, 316–320 (2020).31517724 10.1097/ICO.0000000000002143
21. Kanellopoulos AJ Georgiadou S Asimellis G Objective evaluation of planned versus achieved stromal thickness reduction in myopic femtosecond laser-assisted LASIK J. Refract. Surg. 2015 31 628 632 10.3928/1081597X-20150820-09 26352569
Kanellopoulos, A. J., Georgiadou, S. & Asimellis, G. Objective evaluation of planned versus achieved stromal thickness reduction in myopic femtosecond laser-assisted LASIK. J. Refract. Surg. 31, 628–632 (2015).26352569 10.3928/1081597X-20150820-09
22. Christiansen SM Neuffer MC Sikder S Semnani RT Moshirfar M The effect of preoperative keratometry on visual outcomes after moderate myopic LASIK Clin. Ophthalmol. 2012 6 459 464 22536037
Christiansen, S. M., Neuffer, M. C., Sikder, S., Semnani, R. T. & Moshirfar, M. The effect of preoperative keratometry on visual outcomes after moderate myopic LASIK. Clin. Ophthalmol. 6, 459–464 (2012).22536037
23. Shapira Y Comparison of three epithelial removal techniques in PRK: Mechanical, alcohol-assisted, and transepithelial laser J. Refract. Surg. 2015 31 760 766 10.3928/1081597X-20151021-05 26544564
Shapira, Y. et al. Comparison of three epithelial removal techniques in PRK: Mechanical, alcohol-assisted, and transepithelial laser. J. Refract. Surg. 31, 760–766 (2015).26544564 10.3928/1081597X-20151021-05
24. Borderie M New parameters in assessment of human donor corneal stroma Acta Ophthalmol. 2017 95 e297 e306 10.1111/aos.13351 28133954
Borderie, M. et al. New parameters in assessment of human donor corneal stroma. Acta Ophthalmol. 95, e297–e306 (2017).28133954 10.1111/aos.13351
25. Meek KM Knupp C Corneal structure and transparency Progress Retinal Eye Res. 2015 49 1 16 10.1016/j.preteyeres.2015.07.001
Meek, K. M. & Knupp, C. Corneal structure and transparency. Progress Retinal Eye Res. 49, 1–16 (2015).10.1016/j.preteyeres.2015.07.001
26. Roy AS Dupps WJ Effects of altered corneal stiffness on native and postoperative LASIK corneal biomechanical behavior: A whole-eye finite element analysis J. Refract. Surg. 2009 25 875 887 10.3928/1081597X-20090917-09 19835328
Roy, A. S. & Dupps, W. J. Effects of altered corneal stiffness on native and postoperative LASIK corneal biomechanical behavior: A whole-eye finite element analysis. J. Refract. Surg. 25, 875–887 (2009).19835328 10.3928/1081597X-20090917-09
27. Cao H Jhanji V Wang Y Relationship between postoperative residual refractive error and preoperative corneal stiffness in small-incision lenticule extraction J. Cataract Refract. Surg. 2023 49 942 37379041
Cao, H., Jhanji, V. & Wang, Y. Relationship between postoperative residual refractive error and preoperative corneal stiffness in small-incision lenticule extraction. J. Cataract Refract. Surg. 49, 942 (2023).37379041
28. Georgeon C Corneal and epithelial thickness mapping: Comparison of swept-source- and spectral-domain-optical coherence tomography J. Ophthalmol. 2021 2021 3444083 34650817
Georgeon, C. et al. Corneal and epithelial thickness mapping: Comparison of swept-source- and spectral-domain-optical coherence tomography. J. Ophthalmol. 2021, 3444083 (2021).34650817
