In 2008 Sekundo et al. introduced the minimally invasive small incision lenticule extraction (SMILE), which was published in 2011.1 Unlike in femtosecond laser–assisted LASIK (FS-LASIK), SMILE does not require a flap and the lenticule is extracted via a 2- to 3-mm incision, leaving the remaining anterior stroma and Bowman's layer untouched. SMILE offers potential advantages such as more postoperative comfort and patient satisfaction,2 less postoperative discomfort due to faster corneal healing,3,4 less neurotrophic keratopathy, and a presumed better preservation of biomechanical stability.4–6
Corneal biomechanical properties determine the development of keratectasia. The success of corneal refractive surgery depends on both biological and biomechanical factors. Hence, the better we understand the biomechanical response of corneal tissue after surgery, the more precisely we may predict surgical outcomes and manage postoperative complications. Because SMILE supposedly is superior in preserving corneal integrity when compared to flap-based procedures such as FS-LASIK, it is reasonable to assume that SMILE may also show more biomechanical stability. Reinstein et al.7 elaborated on this hypothesis with a mathematical model estimating the relative differences in postoperative stromal tensile strength following photorefractive keratectomy (PRK), FS-LASIK, and SMILE procedures. Sinha Roy et al.8 suggested an increase in residual stromal stress after FS-LASIK, but not after SMILE procedures. Only a few experimental studies have analyzed differences in the in vivo corneal deformation response following an air-puff,9–15 but did not find a significant difference between FS-LASIK and SMILE procedures, some of which have difficulties in even detecting a biomechanical difference after cross-linking.16 It should be noted that the corneal deformation response following an air-puff is sensitive to changes in corneal thickness17 and intraocular pressure (IOP), which might have masked the subtle differences between FS-LASIK and SMILE in this set-up. In addition, an air-puff directed at the surface of the cornea does not truly represent the force of the IOP that comes from within the eye, neither in terms of the force direction nor under consideration of the cornea's shape being convex on the surface but concave toward the anterior chamber.
Despite the fact that several systems (eg, air-puff tonometers and Brillouin microscopy) have been developed to assess the corneal biomechanical properties in vivo, the most accurate tests are destructive and can only be performed in ex vivo tissue. One-dimensional stress-strain testing is the gold standard technique for ex vivo testing. However, the stress distribution is not representative of the natural stress situation in the eye implied by the IOP. Kling et al.18 developed a set-up for two-dimensional stress-strain testing to overcome this issue. An indenter is used to apply the load similar to the IOP and, simultaneously, the spherical deformation of the corneal sample is recorded. This set-up allows elastic and viscoelastic soft tissue characterization and was previously applied to determine the experimental difference between flap-based and cap-based cornea refractive procedures19 in porcine corneas. In the current study, we used the same setting to experimentally determine the biomechanical differences between FSLASIK and SMILE, to our knowledge for the first time, in human ex vivo fellow eyes.
Materials and Methods
Eleven pairs of human corneas (22 eyes) were obtained from various corneal banks. Due to positive serology of the donor, the corneas were not eligible for transplantation but were approved for research use. The corneas ware equally divided into two groups (11 eyes in each): corneas from the right eye were treated with FS-LASIK and corneas from the left eye with SMILE. Ultrasound pachymetry (Pocket II; Quantel Medical, Cournon d'Auvergne Cedex, France) was performed in each cornea directly before laser refractive surgery. All corneas were treated on the same day.
The corneas were mounted onto an artificial anterior chamber (Katena Products Inc., Denville, NJ) and the IOP was adjusted to approximately 20 mm Hg. For further standardization of the refractive procedure, and given that the epithelium hardly contributes to the mechanical corneal properties,20 the epithelium was scraped off all corneas prior to the laser treatment, ensuring that differences in epithelial transparency did not interfere with the laser beam. The M size contact glass (treatment applanation pack) was used to applanate the cornea by the VisuMax 500-kHz femtosecond laser (Carl Zeiss Meditec AG, Jena, Germany) with the following energy settings: 130 nJ and 4.5 μm track/spot distance. The minimal lenticule thickness was set to 15 μm. All corneas were subjected to a refractive correction of −10.00 diopters (D) sphere and −0.75 D cylinder at 0° with a 7-mm zone using either a 110-μm flap (FSLASIK) or 130-μm cap (SMILE). At the end of the LASIK procedure, the flap was sealed using fibrin glue (Tisseel 2 mL; Baxter, Deerfield, IL). Sealing the flap had two functions: to imitate epithelialization and to prevent the stroma from swelling in the time until the biomechanical measurement was performed. We successfully used the same technique previously in our study on porcine corneas.19,21 Directly after the surgical intervention, the corneoscleral buttons were preserved in Optisol GS (Bausch & Lomb, Rochester, NY) until the biomechanical measurements were performed.
Two-dimensional biomechanical characterization was performed on entire corneoscleral buttons, as described earlier.19,21 Briefly, buttons were mounted circumferentially (10-mm diameter) and a spherical indenter was used to apply the three-dimensional test force from the posterior surface, similar to the IOP (Figure 1). A commercial stress-strain extensometer/indenter (Z0.5; Zwick GmbH & Co., Ulm, Germany) was used for the experiments. Each corneal specimen underwent two cycles of stress-strain preconditioning between 0.03 and 9.0 N (571 kPa stress), corresponding to an IOP between 15 and 4,100 mm Hg, followed by a stress-relaxation test at 9.0 N for 120 sec. The vertical extension was recorded as a function of stress and converted into tensile strain according to the geometrical context (see our previous studies19,21 for detailed equations):
where σ is stress, ∊tensile
is tensile strain, R is the radius of the customized holder, and Δ is the vertical indentation. Stress was computed from the applied test force and the individual central corneal pachymetry of each cornea (ie, homogeneous material properties were assumed and preoperative central corneal thickness was used as a scaling factor to better compare measurements between corneas of different individuals).
Schematic of the measurement set-up used for corneal biomechanical characterization.
Statistical analysis was performed in SPSS software (version 23.0; IBM Corporation, Armonk, NY). Normality was tested with the Shapiro–Wilk test. Subsequently, either a two-tailed paired test or a two-tailed Wilcoxon signed-rank test was applied to detect significant differences between treatment groups. Confidence intervals of 95% were applied.
According to the Shapiro–Wilk test (P = .008), stress-strain data were not normally distributed. Hence, non-parametric statistical analysis was performed using the two-tailed Wilcoxon signed-rank test. Figure 2 presents the stress-strain relationship and the elastic modulus as a function of strain for the different treatment groups. The effective elastic modulus between 0.5% and 2% of strain (Figures 2–3) was 1.47 times higher (P = .003) after SMILE at 8.22 MPa (IQR = 4.76) than after LASIK at 5.59 MPa (IQR = 2.77) refractive correction. The Cohen effect size was large (r = 0.83).
(A) Stress and (B) elastic modulus as a function of strain for corneas treated with small incision lenticule extraction (SMILE) and femtosecond laser–assisted LASIK.
Small incision lenticule extraction (SMILE) is 1.47 times stiffer than femtosecond laser–assisted LASIK.
According to the Shapiro–Wilk test (P = .242), stress-strain data were normally distributed. Hence, parametric statistical analysis was performed using the two-tailed paired t test. No significant differences (P =.658) were observed between treatment groups, with a mean remaining stress of 181 ± 31 kPa after SMILE and 177 ± 26 kPa after LASIK after relaxation. The paired samples did show a significant correlation of 0.647 (P = .031).
With our previous studies,19,21 we could demonstrate, as widely presumed in the refractive community, that the flap-based procedure weakens the cornea more than the cap-based procedure when tested on porcine corneas. In human corneas, we found even greater differences, with corneas after SMILE being 1.47 times stronger compared to corneas after FS-LASIK. The most plausible explanation is the presence of the membrane-like condensed structure of the anterior stroma in human corneas (Bowman's layer), which is virtually absent in porcine corneas. The creation of a flap severs both the Bowman's layer and the anterior, biomechanically stronger, stroma.22
In 2014, a finite element method study8 showed that the mechanical stress distribution after SMILE remains similar to an untreated control cornea of the same geometry, whereas after LASIK the stress in the flap is reduced and the stress in the residual stromal bed is increased, respectively. This suggests that after flap-based procedures such as FS-LASIK, the flap does not contribute to support the IOP any longer and, therefore, the mechanical weakening increases with the flap thickness. In contrast, according to the finite element method simulations, after SMILE the anterior part of the cap is still supporting the remaining cornea and able to take up mechanical stress. Therefore, we may assume that with cap-based surgery the mechanical weakening only depends on the thickness of the lenticule, and not on the thickness of the cap. Our results are in line with these assumptions, showing a stronger mechanical weakening after FS-LASIK than SMILE, given that in FS-LASIK the effective stromal thickness that provides mechanical resistance is reduced.
Reinstein et al.7 calculated the remaining tensile strength of the postoperative human cornea using a mathematical model. They estimated 54% remaining tensile strength after LASIK as compared with 75% after SMILE, assuming a 110-μm flap, a 130-μm cap, and 110-μm of stromal tissue removal. Our study echoes these theoretical results with the differences even more prominent than assumed (Figure 3) when measured ex vivo in human corneas. This difference can be attributed to the fact that we attempted a larger correction compared to Reinstein et al.'s model7 (−10.35 vs −7.75 D) because post-mortem corneas are swollen and the amount of tissue effectively removed in our experiment was definitely less than in living tissue. A recent ex vivo study23 on human eyes reported a similar corneal strength reduction after SMILE and LASIK in higher myopic corrections (−8.00 D) and a higher corneal strength reduction after SMILE in lower myopic corrections (−3.00 D). However, it is important to note that the refractive correction was performed over an optical zone of 6.5 mm, whereas the mechanical test was performed only in the central 3.5 × 3.5 mm area by pulling the corneal buttons laterally, as opposed to the posterior force applied in the current study. This implies that flap and cap were clamped to the stromal bed, which is not comparable to the condition in the patient. In this case, the mechanical difference is expected to be related only to percentage of ablated tissue and not to flap or cap technique.
In our study, despite different post-mortem times and donor ages, a paired-eye study eliminates this sample bias because each treatment group had an equal number of corneas with identical characteristics of age, degree of degeneration, and possible underlying pathologies, finally reducing the source of error and increasing the statistical power.
A limitation for the current study could be the assumption of homogeneous material properties and uniform corneal thickness, which restricted our analysis to the overall tissue weakening but did not allow localized assessment of corneal stiffness. Also, the fibrin-glued flap has a different stability compared to an in vivo epithelialized flap with some degree of scar formation along the flap border. Due to corneal swelling, corneal strain at low testing forces may not have been equally distributed along the corneal tissue. Because both conditions in this study are equally affected, no bias is expected from this factor.
Our ex vivo results on human paired-eye corneas confirm SMILE to better preserve the corneal stress resistance, supporting the mathematical model,7 finite element method,9 and our ex vivo experiments on non-human corneas published previously.19,21 Further prospective non-inferiority clinical studies matched by refraction, treatment zone, age, and sex may be envisaged once more sensitive in vivo techniques for the measurement of the corneal biomechanics become available.
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