Thirty-four patients were treated with femtosecond lenticule extraction (FLEx) in 1 eye and small-incision lenticule extraction (SMILE) in the other eye for moderate to high myopia. The procedures were performed using the ReLEx VisuMax femtosecond laser system. Patients were examined before and 6 months after surgery. Overall, the 37 corneal waveform parameters from the Ocular Response Analyzer biomechanical waveform analyzer were not able to detect major differences in corneal biomechanical properties between the flap-based FLEx procedure and the cap-based SMILE procedure.</p

Hjortdal, Jesper

Ivarsen, Anders R.

Rævdal, Pernille

Vestergaard, Anders H.

English

Syddansk Universitets Forskerportal

       University of Southern DenmarkCorneal biomechanical change assessment using biomechanical waveform analyzerparametersContralateral comparison of eyes having femtosecond lenticule extraction and small-incision lenticule extraction for moderate to high myopiaVestergaard, Anders H.; Rævdal, Pernille; Ivarsen, Anders R.; Hjortdal, JesperPublished in:JCRS Online Case ReportsDOI:10.1016/j.jcro.2018.10.002Publication date:2019Document version:Accepted manuscriptDocument license:CC BY-NC-NDCitation for pulished version (APA):Vestergaard, A. H., Rævdal, P., Ivarsen, A. R., & Hjortdal, J. (2019). Corneal biomechanical change assessmentusing biomechanical waveform analyzer parameters: Contralateral comparison of eyes having femtosecondlenticule extraction and small-incision lenticule extraction for moderate to high myopia. JCRS Online CaseReports, 7(2), 17-19. https://doi.org/10.1016/j.jcro.2018.10.002Go to publication entry in University of Southern Denmark's Research PortalTerms of useThis work is brought to you by the University of Southern Denmark.Unless otherwise specified it has been shared according to the terms for self-archiving.If no other license is stated, these terms apply:            • You may download this work for personal use only.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying this open access versionIf you believe that this document breaches copyright please contact us providing details and we will investigate your claim.Please direct all enquiries to puresupport@bib.sdu.dkDownload date: 21. Oct. 2025 1 Detection of corneal biomechanical changes using waveform parameters from The Ocular Response Analyzer: A contralateral comparison of eyes treated with FLEX and SMILE for moderate to high myopia   Anders H. Vestergaard,1 MD, PhD Pernille Rævdal,1 MD Anders R. Ivarsen,2 MD, PhD Jesper Ø. Hjortdal,2 MD, PhD, DMSci  1Department of Ophthalmology  2Department of Ophthalmology Odense University Hospital   Aarhus University Hospital Sdr. Boulevard 29    Nørrebrogade 44 5000 Odense C    8000 Aarhus C Denmark     Denmark  Corresponding author: Anders H. Vestergaard  Email: vestergaard_anders@hotmail.com Phone: +45 65413196 Fax: +45 66126387  Clinical Trials registration reference number: NCT01673503, at www.clinicaltrials.gov Running head: Case report: FLEX vs. SMILE Financial Support: Hjortdal J.: Travel reimbursement. Other authors: None.  The authors wish to thank the Region of Southern Denmark for supporting this project  2 Abstract:  We report the first paired-eye study to directly compare Ocular Response Analyzer (ORA) derived corneal waveform parameters after the two all-femtosecond laser refractive techniques, ReLEx FLEX (FLEX) and ReLEx SMILE (SMILE).  A total of 34 patients, treated with FLEX in one eye, and SMILE in the other for moderate to high myopia, were examined before and 6 months after surgery. Overall, the 37 corneal waveform parameters from the ORA were not able to detect any major differences in corneal biomechanical properties, between the flap-based FLEX procedure and the cap-based SMILE procedure.      3 Introduction  Corneal refractive eye surgery affects biomechanical properties by reducing the biomechanical strength due to irreversible corneal lamellar changes. Theoretically, the small incision in the ReLEx SMILE technique, should have biomechanical advantages over flap-based techniques such as ReLEx FLEX and Femtosecond LASIK, due to better preservation of the stronger anterior stroma. This has been demonstrated in a mathematical model by Reinstein et al,1 a contralateral computational analysis by Seven et al,2 a finite-element analysis by Roy et al.,3 and in ex vivo porcine eye studies by Spiru et al.4 However, it still remains a challenge to measure the strength and stability of the cornea in vivo and our knowledge on this area is therefore limited.   Only two commercially available devices state to measure the biomechanical proportions of the cornea in vivo, and both machines use non-contact air puff based tonometry; the Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Depew, NY, USA) and the Oculus Corvis ST (CST; Oculus Optik-geräte, Inc., Wetzlar, Germany). The ORA estimates several parameters among which corneal hysteresis (CH) and corneal resistance factor (CRF) are the most prevalent parameters reported when describing corneal viscoelastic properties.5 The devices are especially used for glaucoma, keratoconus screening, and screening of patients before refractive surgery.  In 2014, we published a paired eye study in which eyes were randomized to receive FLEX in one eye and SMILE in the other eye for treatment of moderate to high myopia.6 Amongst other parameters, CH and CRF were determined before and 6 months after surgery, in an attempt to detect changes in corneal biomechanical properties related to the different incision sizes. No statistical significant difference was found between the two techniques in that study. However, at the time we were not in possession of the latest ORA software, so  4 retrieval of the 37 relatively new parameters which describes the waveform of the ORA curve, and the derived keratoconus score, were not available. Hence, the purpose of this subsequent study was to analyze the 37 new waveform parameters and comparing FLEX and SMILE, in an attempt to further quantify changes in corneal biomechanical properties.  Case report  In the original study, 35 patients (70 eyes) were included in a prospective, single-masked, paired-eye study, registered at www.clinicaltrials.gov (identifier: NCT01673503). Patients were randomized to receive FLEX in one eye and SMILE in the other eye for treatment of moderate to high myopia. All patients had stable myopia and no other ocular diseases. A VisuMax® femtosecond laser (Carl Zeiss Meditec, Jena, Germany) was used to make the refractive cut. Lenticule diameters were the same in both eyes and ranged from 6.00 to 6.50 mm. Flap thickness was 110 to 120 µm, and flap/cap diameter ranged from 7.3 to 8.0 mm. All eyes were left with at least 250 microns of residual stromal bed. For further details, please see the original article and study protocol.6  Concerning corneal waveform parameters: An ocular response analyzer uses bi-directional applanation through brief air-pulses to rapidly deform the cornea in- and outwards, measuring intraocular pressure two times independently. An electro-optical system monitors the central 3 mm curvature of the cornea throughout the deformation and generates an ORA response curve. The 37 new parameters describe different areas, heights, widths, slopes, irregularities etc. of the response curve. For this study, the original raw data were anonymized and sent to the manufacturer of the ORA, and here the newer software (version 3.01) was applied and the new waveform parameters derived, including the so-called keratoconus (KC) score.   5 Results  In total, 34 of the 35 patients included in the study, completed the 6 months follow-up period.  No significant difference (p>0.05) between FLEX and SMILE eyes was found at baseline nor after 6 months for all 37 waveform parameters, including the KC-score. Also, no difference was found when the change in each parameter between the preoperative to 6 months postoperative values from both groups was compared, despite a single parameter (w11 = width of peak1 at the base of the peak1 region). Here, a borderline significant difference between the change in FLEX and SMILE after 6 months (p=0.045), in favour of FLEX was found.  A significant difference was found for the majority of all 37 parameters, including the KC-score, in both the FLEX group and the SMILE group, when preoperative and 6 months data were compared. Results are presented in Table 1.  Discussion  All previous published contralateral RCT studies comparing SMILE to FLEX or Femtosecond-LASIK,6,7,8 have failed to demonstrate any differences between the cap-based SMILE technique and the flap-based techniques when evaluating CH or CRF, although some non-randomized studies (e.g. Wu et al9) have found a difference in favour of the SMILE technique.  In an attempt to enhance our knowledge about corneal biomechanical properties, further evaluation of the ORA waveforms was introduced. In theory, the derived waveforms provide a unique fingerprint for each cornea which may be helpful to differentiate between healthy  6 and diseased corneas, although very little is known about the clinical significance of these various waveform parameters.10 In this study, the 37 relative new waveform parameters from the ORA, and the resulting KC score, were not able to detect any major differences between the FLEX and the SMILE procedures. The single parameter with a borderline statistical significant value in favour of FLEX could not be related to any clinical relevant change and is speculated to be a result of the multiple significance tests performed. When doing 37 statistical tests, then 1 to 2 parameters will by chance be statistically different with a standard alpha level of 0.05. After correction of multiple comparisons (Bonferroni) the parameter was no longer statistical significant. The majority of the waveform parameters were significantly reduced after either procedure, indicating a weakening of corneal strength, and the changes were highly related to the changes in CCT, as previously demonstrated by other biomechanical parameters (corneal hysteresis and corneal resistance factor).6 However, the presumed corneal biomechanical advantage of small incision lenticule extraction (SMILE) compared to the flap-based procedure (FLEX) was not found.   The paired-eye design meant that most sources of variability could be neglected when comparing FLEX and SMILE. However, some potential limitations include variability in patient alignment and corneal centration when performing the air-pulse measurements, and also the ocular pulse amplitude.  To our knowledge, this is the first paired-eye study to directly compare ORA derived waveform parameters after the two all-femtosecond laser refractive techniques, FLEX and SMILE.  Future studies should aim for longer follow-up periods to assess the risk of corneal ectasia development over time, but also investigate new in vivo and ex vivo techniques for quantifying corneal biomechanical properties and stability.    7 References  1 Reinstein D. Z., Archer T. J., Randleman J. B. Mathematical model to compare the relative tensile strength of the cornea after PRK, LASIK, and small incision lenticule extraction. J Refract Surg. 2013;29:454-60. 2 Seven I, Vahdati A, Pedersen IB, Vestergaard A, Hjortdal J, Roberts CJ, Dupps WJ Jr. Contralateral Eye Comparison of SMILE and Flap-Based Corneal Refractive Surgery: Computational Analysis of Biomechanical Impact. J Refract Surg. 2017;33(7):444-453. 3 Roy A. S., Dupps W. J., Jr.,  Roberts C. J. Comparison of biomechanical effects of small-incision lenticule extraction and laser in situ keratomileusis: finite-element analysis. J Cataract Refract Surg. 2014;40:971-80. 4 Spiru B., Kling S., Hafezi F., Sekundo W. Biomechanical Differences Between Femtosecond Lenticule Extraction (FLEx) and Small Incision Lenticule Extraction (SmILE) Tested by 2D-Extensometry in Ex Vivo Porcine Eyes. Invest Ophthalmol Vis Sci. 2017;58:2591-2595. 5 Luce, D. A. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg. 2005;31:156-62. 6 Vestergaard A. H., Grauslund J., Ivarsen A. R., Hjortdal J. Ø. Central corneal sublayer pachymetry and biomechanical properties after refractive femtosecond lenticule extraction. J Refract Surg. 2014;30:102-8. 7 Agca A., Ozgurhan, E. B., Demirok A., Bozkurt E., Celik U., Ozkaya A., Cankaya I., Yilmaz O. F. Comparison of corneal hysteresis and corneal resistance factor after small incision lenticule extraction and femtosecond laser-assisted LASIK: a prospective fellow eye study. Cont Lens Anterior Eye. 2014;37:77-80.  8 8 Kamiya K., Shimizu K., Igarashi A., Kobashi H., Sato N., Ishii R. Intraindividual comparison of changes in corneal biomechanical parameters after femtosecond lenticule extraction and small-incision lenticule extraction. J Cataract Refract Surg, 2014;40:963-70. 9 Wu D., Wang Y., Zhang L., Wei S. & Tang X. Corneal biomechanical effects: small-incision lenticule extraction versus femtosecond laser-assisted laser in situ keratomileusis. J Cataract Refract Surg. 2014;40:954-62. 10 Zarei-Ghanavati S, Ramirez-Miranda A, Yu F, Hamilton DR. Corneal deformation signal waveform analysis in keratoconic versus post-femtosecond laser in situ keratomileusis eyes after statistical correction for potentially confounding factors. J Cataract Refract Surg. 2012;38(4):607-14.  ORA parameter SMILE FLEX P-values Pre-op mean score 6 months mean score Difference  Pre-op mean score 6 months mean score Difference Pre vs Pre 6 m vs 6 m Diff vs Diff aindex 9.1 8.9 0.2 9.4 8.8* 0.7 0.063 0.389 0.247 bindex 9.5 9.1 0.4 9.7 9.6 0.1 0.895 0.180 0.271 p1area 5579.2 2818.0* 2761.2 5425.7 2923.9* 2501.8 0.495 0.433 0.254 p2area 3096.6 1841.9* 1254.6 3374.4 1865.1* 1509.3 0.244 0.870 0.199 aspect1 27.0 25.2 1.8 28.0 25.7 2.3 0.343 0.821 0.773 aspect2 26.6 26.1 0.6 27.3 29.2 -1.9 0.663 0.265 0.708 uslope1 99.5 116.0* -16.5 101.7 112.2 -10.5 0.354 0.496 0.572 uslope2 111.3 130.7 -19.4 123.7 139.2 -15.5 0.308 0.528 0.826 dslope1 38.8 33.7* 5.1 40.1 34.5* 5.6 0.427 0.528 0.966 dslope2 35.9 33.8 2.1 36.0 38.2 -2.2 0.663 0.155 0.422 w1 21.8 18.5* 3.3 21.4 18.9* 2.5 0.511 0.633 0.415 w2 17.7 14.6* 3.1 18.3 13.3* 5.0 0.557 0.157 0.115 h1 579.2 449.6* 129.6 594.5 458.3* 136.2 0.632 0.653 0.767 h2 433.5 336.6* 96.9 460.4 367.4* 93.0 0.351 0.200 0.899 dive1 483.0 400.6* 82.4 516.3 389.9* 126.4 0.259 0.579 0.102 dive2 345.9 233.6* 112.3 372.5 268.4* 104.0 0.335 0.150 0.774 path1 20.7 31.5* -10.9 21.9 30.8* -8.9 0.146 0.600 0.251 path2 26.4 33.1* -6.7 25.4 35.0* -9.6 0.354 0.241 0.187 mslew1 177.3 165.7 11.6 174.3 163.6 10.7 0.744 0.699 0.953 mslew2 171.7 179.4 -7.7 184.0 199.5 -15.5 0.473 0.193 0.733 slew1 97.6 118.2* -20.6 102.3 113.9 -11.6 0.244 0.648 0.438 slew2 112.3 131.6 -19.3 124.8 142.2 -17.5 0.295 0.407 0.918 aplhf 1.3 1.3 -0.1 1.3 1.4 -0.1 0.852 0.524 0.453 p1area1 2517.4 1109.5* 1407.9 2380.1 1137.7* 1242.4 0.321 0.496 0.246 p2area1 1346.8 765.9* 580.9 1474.8 778.6* 696.2 0.237 0.834 0.210 aspect11 33.9 46.0* -12.1 38.2 44.4 -6.2 0.068 0.651 0.191 aspect21 35.6 39.8 -4.3 38.2 44.3 -6.1 0.477 0.315 0.763 uslope11 88.5 110.1* -21.6 98.2 106.8 -8.6 0.133 0.716 0.272 uslope21 92.3 97.4 -5.1 100.7 107.9 -7.2 0.347 0.416 0.901 dslope11 58.1 80.2* -22.1 62.8 79.0* -16.2 0.773 0.82 0.573 dslope21 56.1 59.5 -3.5 57.6 67.3 -9.7 0.394 0.154 0.550 w11 11.8 6.9* 4.8 10.9 7.4* 3.5 0.103 0.18 0.045 w21 8.8 6.5* 2.3 8.7 6.1* 2.6 0.817 0.662 0.966 h11 386.2 299.7* 86.4 396.3 305.5* 90.8 0.632 0.653 0.767 h21 289.0 224.4* 64.6 307.0 244.9* 62.0 0.351 0.200 0.899 path11 29.0 45.8* -16.7 30.6 46.8* -16.2 0.317 0.699 0.890 path21 36.6 43.3* -6.8 33.9 45.8* -11.9 0.148 0.348 0.105 KC-score 1.2 0.6* 0.6 1.3 0.6* 0.7 0.284 0.491 0.657 Table 1. Waveform parameters including keratoconus score (KC-score) from the Ocular Response Analyzer for 34 patients treated with ReLEX FLEX in one eye and ReLEx SMILE in the other.   * indicates p<0.05 when pre-operative values and 6 months post-operative values are compared.                    

Corneal biomechanical change assessment using biomechanical waveform analyzer parameters:Contralateral comparison of eyes having femtosecond lenticule extraction and small-incision lenticule extraction for moderate to high myopia

       University of Southern DenmarkCorneal biomechanical change assessment using biomechanical waveform analyzerparametersContralateral comparison of eyes having femtosecond lenticule extraction and small-incision lenticule extraction for moderate to high myopiaVestergaard, Anders H.; Rævdal, Pernille; Ivarsen, Anders R.; Hjortdal, JesperPublished in:JCRS Online Case ReportsDOI:10.1016/j.jcro.2018.10.002Publication date:2019Document version:Accepted manuscriptDocument license:CC BY-NC-NDCitation for pulished version (APA):Vestergaard, A. H., Rævdal, P., Ivarsen, A. R., & Hjortdal, J. (2019). Corneal biomechanical change assessmentusing biomechanical waveform analyzer parameters: Contralateral comparison of eyes having femtosecondlenticule extraction and small-incision lenticule extraction for moderate to high myopia. JCRS Online CaseReports, 7(2), 17-19. https://doi.org/10.1016/j.jcro.2018.10.002Go to publication entry in University of Southern Denmark's Research PortalTerms of useThis work is brought to you by the University of Southern Denmark.Unless otherwise specified it has been shared according to the terms for self-archiving.If no other license is stated, these terms apply:            • You may download this work for personal use only.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying this open access versionIf you believe that this document breaches copyright please contact us providing details and we will investigate your claim.Please direct all enquiries to puresupport@bib.sdu.dkDownload date: 25. Oct. 2025 1 Detection of corneal biomechanical changes using waveform parameters from The Ocular Response Analyzer: A contralateral comparison of eyes treated with FLEX and SMILE for moderate to high myopia   Anders H. Vestergaard,1 MD, PhD Pernille Rævdal,1 MD Anders R. Ivarsen,2 MD, PhD Jesper Ø. Hjortdal,2 MD, PhD, DMSci  1Department of Ophthalmology  2Department of Ophthalmology Odense University Hospital   Aarhus University Hospital Sdr. Boulevard 29    Nørrebrogade 44 5000 Odense C    8000 Aarhus C Denmark     Denmark  Corresponding author: Anders H. Vestergaard  Email: vestergaard_anders@hotmail.com Phone: +45 65413196 Fax: +45 66126387  Clinical Trials registration reference number: NCT01673503, at www.clinicaltrials.gov Running head: Case report: FLEX vs. SMILE Financial Support: Hjortdal J.: Travel reimbursement. Other authors: None.  The authors wish to thank the Region of Southern Denmark for supporting this project  2 Abstract:  We report the first paired-eye study to directly compare Ocular Response Analyzer (ORA) derived corneal waveform parameters after the two all-femtosecond laser refractive techniques, ReLEx FLEX (FLEX) and ReLEx SMILE (SMILE).  A total of 34 patients, treated with FLEX in one eye, and SMILE in the other for moderate to high myopia, were examined before and 6 months after surgery. Overall, the 37 corneal waveform parameters from the ORA were not able to detect any major differences in corneal biomechanical properties, between the flap-based FLEX procedure and the cap-based SMILE procedure.      3 Introduction  Corneal refractive eye surgery affects biomechanical properties by reducing the biomechanical strength due to irreversible corneal lamellar changes. Theoretically, the small incision in the ReLEx SMILE technique, should have biomechanical advantages over flap-based techniques such as ReLEx FLEX and Femtosecond LASIK, due to better preservation of the stronger anterior stroma. This has been demonstrated in a mathematical model by Reinstein et al,1 a contralateral computational analysis by Seven et al,2 a finite-element analysis by Roy et al.,3 and in ex vivo porcine eye studies by Spiru et al.4 However, it still remains a challenge to measure the strength and stability of the cornea in vivo and our knowledge on this area is therefore limited.   Only two commercially available devices state to measure the biomechanical proportions of the cornea in vivo, and both machines use non-contact air puff based tonometry; the Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Depew, NY, USA) and the Oculus Corvis ST (CST; Oculus Optik-geräte, Inc., Wetzlar, Germany). The ORA estimates several parameters among which corneal hysteresis (CH) and corneal resistance factor (CRF) are the most prevalent parameters reported when describing corneal viscoelastic properties.5 The devices are especially used for glaucoma, keratoconus screening, and screening of patients before refractive surgery.  In 2014, we published a paired eye study in which eyes were randomized to receive FLEX in one eye and SMILE in the other eye for treatment of moderate to high myopia.6 Amongst other parameters, CH and CRF were determined before and 6 months after surgery, in an attempt to detect changes in corneal biomechanical properties related to the different incision sizes. No statistical significant difference was found between the two techniques in that study. However, at the time we were not in possession of the latest ORA software, so  4 retrieval of the 37 relatively new parameters which describes the waveform of the ORA curve, and the derived keratoconus score, were not available. Hence, the purpose of this subsequent study was to analyze the 37 new waveform parameters and comparing FLEX and SMILE, in an attempt to further quantify changes in corneal biomechanical properties.  Case report  In the original study, 35 patients (70 eyes) were included in a prospective, single-masked, paired-eye study, registered at www.clinicaltrials.gov (identifier: NCT01673503). Patients were randomized to receive FLEX in one eye and SMILE in the other eye for treatment of moderate to high myopia. All patients had stable myopia and no other ocular diseases. A VisuMax® femtosecond laser (Carl Zeiss Meditec, Jena, Germany) was used to make the refractive cut. Lenticule diameters were the same in both eyes and ranged from 6.00 to 6.50 mm. Flap thickness was 110 to 120 µm, and flap/cap diameter ranged from 7.3 to 8.0 mm. All eyes were left with at least 250 microns of residual stromal bed. For further details, please see the original article and study protocol.6  Concerning corneal waveform parameters: An ocular response analyzer uses bi-directional applanation through brief air-pulses to rapidly deform the cornea in- and outwards, measuring intraocular pressure two times independently. An electro-optical system monitors the central 3 mm curvature of the cornea throughout the deformation and generates an ORA response curve. The 37 new parameters describe different areas, heights, widths, slopes, irregularities etc. of the response curve. For this study, the original raw data were anonymized and sent to the manufacturer of the ORA, and here the newer software (version 3.01) was applied and the new waveform parameters derived, including the so-called keratoconus (KC) score.   5 Results  In total, 34 of the 35 patients included in the study, completed the 6 months follow-up period.  No significant difference (p>0.05) between FLEX and SMILE eyes was found at baseline nor after 6 months for all 37 waveform parameters, including the KC-score. Also, no difference was found when the change in each parameter between the preoperative to 6 months postoperative values from both groups was compared, despite a single parameter (w11 = width of peak1 at the base of the peak1 region). Here, a borderline significant difference between the change in FLEX and SMILE after 6 months (p=0.045), in favour of FLEX was found.  A significant difference was found for the majority of all 37 parameters, including the KC-score, in both the FLEX group and the SMILE group, when preoperative and 6 months data were compared. Results are presented in Table 1.  Discussion  All previous published contralateral RCT studies comparing SMILE to FLEX or Femtosecond-LASIK,6,7,8 have failed to demonstrate any differences between the cap-based SMILE technique and the flap-based techniques when evaluating CH or CRF, although some non-randomized studies (e.g. Wu et al9) have found a difference in favour of the SMILE technique.  In an attempt to enhance our knowledge about corneal biomechanical properties, further evaluation of the ORA waveforms was introduced. In theory, the derived waveforms provide a unique fingerprint for each cornea which may be helpful to differentiate between healthy  6 and diseased corneas, although very little is known about the clinical significance of these various waveform parameters.10 In this study, the 37 relative new waveform parameters from the ORA, and the resulting KC score, were not able to detect any major differences between the FLEX and the SMILE procedures. The single parameter with a borderline statistical significant value in favour of FLEX could not be related to any clinical relevant change and is speculated to be a result of the multiple significance tests performed. When doing 37 statistical tests, then 1 to 2 parameters will by chance be statistically different with a standard alpha level of 0.05. After correction of multiple comparisons (Bonferroni) the parameter was no longer statistical significant. The majority of the waveform parameters were significantly reduced after either procedure, indicating a weakening of corneal strength, and the changes were highly related to the changes in CCT, as previously demonstrated by other biomechanical parameters (corneal hysteresis and corneal resistance factor).6 However, the presumed corneal biomechanical advantage of small incision lenticule extraction (SMILE) compared to the flap-based procedure (FLEX) was not found.   The paired-eye design meant that most sources of variability could be neglected when comparing FLEX and SMILE. However, some potential limitations include variability in patient alignment and corneal centration when performing the air-pulse measurements, and also the ocular pulse amplitude.  To our knowledge, this is the first paired-eye study to directly compare ORA derived waveform parameters after the two all-femtosecond laser refractive techniques, FLEX and SMILE.  Future studies should aim for longer follow-up periods to assess the risk of corneal ectasia development over time, but also investigate new in vivo and ex vivo techniques for quantifying corneal biomechanical properties and stability.    7 References  1 Reinstein D. Z., Archer T. J., Randleman J. B. Mathematical model to compare the relative tensile strength of the cornea after PRK, LASIK, and small incision lenticule extraction. J Refract Surg. 2013;29:454-60. 2 Seven I, Vahdati A, Pedersen IB, Vestergaard A, Hjortdal J, Roberts CJ, Dupps WJ Jr. Contralateral Eye Comparison of SMILE and Flap-Based Corneal Refractive Surgery: Computational Analysis of Biomechanical Impact. J Refract Surg. 2017;33(7):444-453. 3 Roy A. S., Dupps W. J., Jr.,  Roberts C. J. Comparison of biomechanical effects of small-incision lenticule extraction and laser in situ keratomileusis: finite-element analysis. J Cataract Refract Surg. 2014;40:971-80. 4 Spiru B., Kling S., Hafezi F., Sekundo W. Biomechanical Differences Between Femtosecond Lenticule Extraction (FLEx) and Small Incision Lenticule Extraction (SmILE) Tested by 2D-Extensometry in Ex Vivo Porcine Eyes. Invest Ophthalmol Vis Sci. 2017;58:2591-2595. 5 Luce, D. A. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg. 2005;31:156-62. 6 Vestergaard A. H., Grauslund J., Ivarsen A. R., Hjortdal J. Ø. Central corneal sublayer pachymetry and biomechanical properties after refractive femtosecond lenticule extraction. J Refract Surg. 2014;30:102-8. 7 Agca A., Ozgurhan, E. B., Demirok A., Bozkurt E., Celik U., Ozkaya A., Cankaya I., Yilmaz O. F. Comparison of corneal hysteresis and corneal resistance factor after small incision lenticule extraction and femtosecond laser-assisted LASIK: a prospective fellow eye study. Cont Lens Anterior Eye. 2014;37:77-80.  8 8 Kamiya K., Shimizu K., Igarashi A., Kobashi H., Sato N., Ishii R. Intraindividual comparison of changes in corneal biomechanical parameters after femtosecond lenticule extraction and small-incision lenticule extraction. J Cataract Refract Surg, 2014;40:963-70. 9 Wu D., Wang Y., Zhang L., Wei S. & Tang X. Corneal biomechanical effects: small-incision lenticule extraction versus femtosecond laser-assisted laser in situ keratomileusis. J Cataract Refract Surg. 2014;40:954-62. 10 Zarei-Ghanavati S, Ramirez-Miranda A, Yu F, Hamilton DR. Corneal deformation signal waveform analysis in keratoconic versus post-femtosecond laser in situ keratomileusis eyes after statistical correction for potentially confounding factors. J Cataract Refract Surg. 2012;38(4):607-14.  ORA parameter SMILE FLEX P-values Pre-op mean score 6 months mean score Difference  Pre-op mean score 6 months mean score Difference Pre vs Pre 6 m vs 6 m Diff vs Diff aindex 9.1 8.9 0.2 9.4 8.8* 0.7 0.063 0.389 0.247 bindex 9.5 9.1 0.4 9.7 9.6 0.1 0.895 0.180 0.271 p1area 5579.2 2818.0* 2761.2 5425.7 2923.9* 2501.8 0.495 0.433 0.254 p2area 3096.6 1841.9* 1254.6 3374.4 1865.1* 1509.3 0.244 0.870 0.199 aspect1 27.0 25.2 1.8 28.0 25.7 2.3 0.343 0.821 0.773 aspect2 26.6 26.1 0.6 27.3 29.2 -1.9 0.663 0.265 0.708 uslope1 99.5 116.0* -16.5 101.7 112.2 -10.5 0.354 0.496 0.572 uslope2 111.3 130.7 -19.4 123.7 139.2 -15.5 0.308 0.528 0.826 dslope1 38.8 33.7* 5.1 40.1 34.5* 5.6 0.427 0.528 0.966 dslope2 35.9 33.8 2.1 36.0 38.2 -2.2 0.663 0.155 0.422 w1 21.8 18.5* 3.3 21.4 18.9* 2.5 0.511 0.633 0.415 w2 17.7 14.6* 3.1 18.3 13.3* 5.0 0.557 0.157 0.115 h1 579.2 449.6* 129.6 594.5 458.3* 136.2 0.632 0.653 0.767 h2 433.5 336.6* 96.9 460.4 367.4* 93.0 0.351 0.200 0.899 dive1 483.0 400.6* 82.4 516.3 389.9* 126.4 0.259 0.579 0.102 dive2 345.9 233.6* 112.3 372.5 268.4* 104.0 0.335 0.150 0.774 path1 20.7 31.5* -10.9 21.9 30.8* -8.9 0.146 0.600 0.251 path2 26.4 33.1* -6.7 25.4 35.0* -9.6 0.354 0.241 0.187 mslew1 177.3 165.7 11.6 174.3 163.6 10.7 0.744 0.699 0.953 mslew2 171.7 179.4 -7.7 184.0 199.5 -15.5 0.473 0.193 0.733 slew1 97.6 118.2* -20.6 102.3 113.9 -11.6 0.244 0.648 0.438 slew2 112.3 131.6 -19.3 124.8 142.2 -17.5 0.295 0.407 0.918 aplhf 1.3 1.3 -0.1 1.3 1.4 -0.1 0.852 0.524 0.453 p1area1 2517.4 1109.5* 1407.9 2380.1 1137.7* 1242.4 0.321 0.496 0.246 p2area1 1346.8 765.9* 580.9 1474.8 778.6* 696.2 0.237 0.834 0.210 aspect11 33.9 46.0* -12.1 38.2 44.4 -6.2 0.068 0.651 0.191 aspect21 35.6 39.8 -4.3 38.2 44.3 -6.1 0.477 0.315 0.763 uslope11 88.5 110.1* -21.6 98.2 106.8 -8.6 0.133 0.716 0.272 uslope21 92.3 97.4 -5.1 100.7 107.9 -7.2 0.347 0.416 0.901 dslope11 58.1 80.2* -22.1 62.8 79.0* -16.2 0.773 0.82 0.573 dslope21 56.1 59.5 -3.5 57.6 67.3 -9.7 0.394 0.154 0.550 w11 11.8 6.9* 4.8 10.9 7.4* 3.5 0.103 0.18 0.045 w21 8.8 6.5* 2.3 8.7 6.1* 2.6 0.817 0.662 0.966 h11 386.2 299.7* 86.4 396.3 305.5* 90.8 0.632 0.653 0.767 h21 289.0 224.4* 64.6 307.0 244.9* 62.0 0.351 0.200 0.899 path11 29.0 45.8* -16.7 30.6 46.8* -16.2 0.317 0.699 0.890 path21 36.6 43.3* -6.8 33.9 45.8* -11.9 0.148 0.348 0.105 KC-score 1.2 0.6* 0.6 1.3 0.6* 0.7 0.284 0.491 0.657 Table 1. Waveform parameters including keratoconus score (KC-score) from the Ocular Response Analyzer for 34 patients treated with ReLEX FLEX in one eye and ReLEx SMILE in the other.   * indicates p<0.05 when pre-operative values and 6 months post-operative values are compared.                    

       University of Southern DenmarkCorneal biomechanical change assessment using biomechanical waveform analyzerparametersContralateral comparison of eyes having femtosecond lenticule extraction and small-incision lenticule extraction for moderate to high myopiaVestergaard, Anders H.; Rævdal, Pernille; Ivarsen, Anders R.; Hjortdal, JesperPublished in:JCRS Online Case ReportsDOI:10.1016/j.jcro.2018.10.002Publication date:2019Document version:Accepted manuscriptDocument license:CC BY-NC-NDCitation for pulished version (APA):Vestergaard, A. H., Rævdal, P., Ivarsen, A. R., & Hjortdal, J. (2019). Corneal biomechanical change assessmentusing biomechanical waveform analyzer parameters: Contralateral comparison of eyes having femtosecondlenticule extraction and small-incision lenticule extraction for moderate to high myopia. JCRS Online CaseReports, 7(2), 17-19. https://doi.org/10.1016/j.jcro.2018.10.002Go to publication entry in University of Southern Denmark's Research PortalTerms of useThis work is brought to you by the University of Southern Denmark.Unless otherwise specified it has been shared according to the terms for self-archiving.If no other license is stated, these terms apply:            • You may download this work for personal use only.            • You may not further distribute the material or use it for any profit-making activity or commercial gain            • You may freely distribute the URL identifying this open access versionIf you believe that this document breaches copyright please contact us providing details and we will investigate your claim.Please direct all enquiries to puresupport@bib.sdu.dkDownload date: 23. Oct. 2025 1 Detection of corneal biomechanical changes using waveform parameters from The Ocular Response Analyzer: A contralateral comparison of eyes treated with FLEX and SMILE for moderate to high myopia   Anders H. Vestergaard,1 MD, PhD Pernille Rævdal,1 MD Anders R. Ivarsen,2 MD, PhD Jesper Ø. Hjortdal,2 MD, PhD, DMSci  1Department of Ophthalmology  2Department of Ophthalmology Odense University Hospital   Aarhus University Hospital Sdr. Boulevard 29    Nørrebrogade 44 5000 Odense C    8000 Aarhus C Denmark     Denmark  Corresponding author: Anders H. Vestergaard  Email: vestergaard_anders@hotmail.com Phone: +45 65413196 Fax: +45 66126387  Clinical Trials registration reference number: NCT01673503, at www.clinicaltrials.gov Running head: Case report: FLEX vs. SMILE Financial Support: Hjortdal J.: Travel reimbursement. Other authors: None.  The authors wish to thank the Region of Southern Denmark for supporting this project  2 Abstract:  We report the first paired-eye study to directly compare Ocular Response Analyzer (ORA) derived corneal waveform parameters after the two all-femtosecond laser refractive techniques, ReLEx FLEX (FLEX) and ReLEx SMILE (SMILE).  A total of 34 patients, treated with FLEX in one eye, and SMILE in the other for moderate to high myopia, were examined before and 6 months after surgery. Overall, the 37 corneal waveform parameters from the ORA were not able to detect any major differences in corneal biomechanical properties, between the flap-based FLEX procedure and the cap-based SMILE procedure.      3 Introduction  Corneal refractive eye surgery affects biomechanical properties by reducing the biomechanical strength due to irreversible corneal lamellar changes. Theoretically, the small incision in the ReLEx SMILE technique, should have biomechanical advantages over flap-based techniques such as ReLEx FLEX and Femtosecond LASIK, due to better preservation of the stronger anterior stroma. This has been demonstrated in a mathematical model by Reinstein et al,1 a contralateral computational analysis by Seven et al,2 a finite-element analysis by Roy et al.,3 and in ex vivo porcine eye studies by Spiru et al.4 However, it still remains a challenge to measure the strength and stability of the cornea in vivo and our knowledge on this area is therefore limited.   Only two commercially available devices state to measure the biomechanical proportions of the cornea in vivo, and both machines use non-contact air puff based tonometry; the Ocular Response Analyzer (ORA; Reichert Ophthalmic Instruments, Depew, NY, USA) and the Oculus Corvis ST (CST; Oculus Optik-geräte, Inc., Wetzlar, Germany). The ORA estimates several parameters among which corneal hysteresis (CH) and corneal resistance factor (CRF) are the most prevalent parameters reported when describing corneal viscoelastic properties.5 The devices are especially used for glaucoma, keratoconus screening, and screening of patients before refractive surgery.  In 2014, we published a paired eye study in which eyes were randomized to receive FLEX in one eye and SMILE in the other eye for treatment of moderate to high myopia.6 Amongst other parameters, CH and CRF were determined before and 6 months after surgery, in an attempt to detect changes in corneal biomechanical properties related to the different incision sizes. No statistical significant difference was found between the two techniques in that study. However, at the time we were not in possession of the latest ORA software, so  4 retrieval of the 37 relatively new parameters which describes the waveform of the ORA curve, and the derived keratoconus score, were not available. Hence, the purpose of this subsequent study was to analyze the 37 new waveform parameters and comparing FLEX and SMILE, in an attempt to further quantify changes in corneal biomechanical properties.  Case report  In the original study, 35 patients (70 eyes) were included in a prospective, single-masked, paired-eye study, registered at www.clinicaltrials.gov (identifier: NCT01673503). Patients were randomized to receive FLEX in one eye and SMILE in the other eye for treatment of moderate to high myopia. All patients had stable myopia and no other ocular diseases. A VisuMax® femtosecond laser (Carl Zeiss Meditec, Jena, Germany) was used to make the refractive cut. Lenticule diameters were the same in both eyes and ranged from 6.00 to 6.50 mm. Flap thickness was 110 to 120 µm, and flap/cap diameter ranged from 7.3 to 8.0 mm. All eyes were left with at least 250 microns of residual stromal bed. For further details, please see the original article and study protocol.6  Concerning corneal waveform parameters: An ocular response analyzer uses bi-directional applanation through brief air-pulses to rapidly deform the cornea in- and outwards, measuring intraocular pressure two times independently. An electro-optical system monitors the central 3 mm curvature of the cornea throughout the deformation and generates an ORA response curve. The 37 new parameters describe different areas, heights, widths, slopes, irregularities etc. of the response curve. For this study, the original raw data were anonymized and sent to the manufacturer of the ORA, and here the newer software (version 3.01) was applied and the new waveform parameters derived, including the so-called keratoconus (KC) score.   5 Results  In total, 34 of the 35 patients included in the study, completed the 6 months follow-up period.  No significant difference (p>0.05) between FLEX and SMILE eyes was found at baseline nor after 6 months for all 37 waveform parameters, including the KC-score. Also, no difference was found when the change in each parameter between the preoperative to 6 months postoperative values from both groups was compared, despite a single parameter (w11 = width of peak1 at the base of the peak1 region). Here, a borderline significant difference between the change in FLEX and SMILE after 6 months (p=0.045), in favour of FLEX was found.  A significant difference was found for the majority of all 37 parameters, including the KC-score, in both the FLEX group and the SMILE group, when preoperative and 6 months data were compared. Results are presented in Table 1.  Discussion  All previous published contralateral RCT studies comparing SMILE to FLEX or Femtosecond-LASIK,6,7,8 have failed to demonstrate any differences between the cap-based SMILE technique and the flap-based techniques when evaluating CH or CRF, although some non-randomized studies (e.g. Wu et al9) have found a difference in favour of the SMILE technique.  In an attempt to enhance our knowledge about corneal biomechanical properties, further evaluation of the ORA waveforms was introduced. In theory, the derived waveforms provide a unique fingerprint for each cornea which may be helpful to differentiate between healthy  6 and diseased corneas, although very little is known about the clinical significance of these various waveform parameters.10 In this study, the 37 relative new waveform parameters from the ORA, and the resulting KC score, were not able to detect any major differences between the FLEX and the SMILE procedures. The single parameter with a borderline statistical significant value in favour of FLEX could not be related to any clinical relevant change and is speculated to be a result of the multiple significance tests performed. When doing 37 statistical tests, then 1 to 2 parameters will by chance be statistically different with a standard alpha level of 0.05. After correction of multiple comparisons (Bonferroni) the parameter was no longer statistical significant. The majority of the waveform parameters were significantly reduced after either procedure, indicating a weakening of corneal strength, and the changes were highly related to the changes in CCT, as previously demonstrated by other biomechanical parameters (corneal hysteresis and corneal resistance factor).6 However, the presumed corneal biomechanical advantage of small incision lenticule extraction (SMILE) compared to the flap-based procedure (FLEX) was not found.   The paired-eye design meant that most sources of variability could be neglected when comparing FLEX and SMILE. However, some potential limitations include variability in patient alignment and corneal centration when performing the air-pulse measurements, and also the ocular pulse amplitude.  To our knowledge, this is the first paired-eye study to directly compare ORA derived waveform parameters after the two all-femtosecond laser refractive techniques, FLEX and SMILE.  Future studies should aim for longer follow-up periods to assess the risk of corneal ectasia development over time, but also investigate new in vivo and ex vivo techniques for quantifying corneal biomechanical properties and stability.    7 References  1 Reinstein D. Z., Archer T. J., Randleman J. B. Mathematical model to compare the relative tensile strength of the cornea after PRK, LASIK, and small incision lenticule extraction. J Refract Surg. 2013;29:454-60. 2 Seven I, Vahdati A, Pedersen IB, Vestergaard A, Hjortdal J, Roberts CJ, Dupps WJ Jr. Contralateral Eye Comparison of SMILE and Flap-Based Corneal Refractive Surgery: Computational Analysis of Biomechanical Impact. J Refract Surg. 2017;33(7):444-453. 3 Roy A. S., Dupps W. J., Jr.,  Roberts C. J. Comparison of biomechanical effects of small-incision lenticule extraction and laser in situ keratomileusis: finite-element analysis. J Cataract Refract Surg. 2014;40:971-80. 4 Spiru B., Kling S., Hafezi F., Sekundo W. Biomechanical Differences Between Femtosecond Lenticule Extraction (FLEx) and Small Incision Lenticule Extraction (SmILE) Tested by 2D-Extensometry in Ex Vivo Porcine Eyes. Invest Ophthalmol Vis Sci. 2017;58:2591-2595. 5 Luce, D. A. Determining in vivo biomechanical properties of the cornea with an ocular response analyzer. J Cataract Refract Surg. 2005;31:156-62. 6 Vestergaard A. H., Grauslund J., Ivarsen A. R., Hjortdal J. Ø. Central corneal sublayer pachymetry and biomechanical properties after refractive femtosecond lenticule extraction. J Refract Surg. 2014;30:102-8. 7 Agca A., Ozgurhan, E. B., Demirok A., Bozkurt E., Celik U., Ozkaya A., Cankaya I., Yilmaz O. F. Comparison of corneal hysteresis and corneal resistance factor after small incision lenticule extraction and femtosecond laser-assisted LASIK: a prospective fellow eye study. Cont Lens Anterior Eye. 2014;37:77-80.  8 8 Kamiya K., Shimizu K., Igarashi A., Kobashi H., Sato N., Ishii R. Intraindividual comparison of changes in corneal biomechanical parameters after femtosecond lenticule extraction and small-incision lenticule extraction. J Cataract Refract Surg, 2014;40:963-70. 9 Wu D., Wang Y., Zhang L., Wei S. & Tang X. Corneal biomechanical effects: small-incision lenticule extraction versus femtosecond laser-assisted laser in situ keratomileusis. J Cataract Refract Surg. 2014;40:954-62. 10 Zarei-Ghanavati S, Ramirez-Miranda A, Yu F, Hamilton DR. Corneal deformation signal waveform analysis in keratoconic versus post-femtosecond laser in situ keratomileusis eyes after statistical correction for potentially confounding factors. J Cataract Refract Surg. 2012;38(4):607-14.  ORA parameter SMILE FLEX P-values Pre-op mean score 6 months mean score Difference  Pre-op mean score 6 months mean score Difference Pre vs Pre 6 m vs 6 m Diff vs Diff aindex 9.1 8.9 0.2 9.4 8.8* 0.7 0.063 0.389 0.247 bindex 9.5 9.1 0.4 9.7 9.6 0.1 0.895 0.180 0.271 p1area 5579.2 2818.0* 2761.2 5425.7 2923.9* 2501.8 0.495 0.433 0.254 p2area 3096.6 1841.9* 1254.6 3374.4 1865.1* 1509.3 0.244 0.870 0.199 aspect1 27.0 25.2 1.8 28.0 25.7 2.3 0.343 0.821 0.773 aspect2 26.6 26.1 0.6 27.3 29.2 -1.9 0.663 0.265 0.708 uslope1 99.5 116.0* -16.5 101.7 112.2 -10.5 0.354 0.496 0.572 uslope2 111.3 130.7 -19.4 123.7 139.2 -15.5 0.308 0.528 0.826 dslope1 38.8 33.7* 5.1 40.1 34.5* 5.6 0.427 0.528 0.966 dslope2 35.9 33.8 2.1 36.0 38.2 -2.2 0.663 0.155 0.422 w1 21.8 18.5* 3.3 21.4 18.9* 2.5 0.511 0.633 0.415 w2 17.7 14.6* 3.1 18.3 13.3* 5.0 0.557 0.157 0.115 h1 579.2 449.6* 129.6 594.5 458.3* 136.2 0.632 0.653 0.767 h2 433.5 336.6* 96.9 460.4 367.4* 93.0 0.351 0.200 0.899 dive1 483.0 400.6* 82.4 516.3 389.9* 126.4 0.259 0.579 0.102 dive2 345.9 233.6* 112.3 372.5 268.4* 104.0 0.335 0.150 0.774 path1 20.7 31.5* -10.9 21.9 30.8* -8.9 0.146 0.600 0.251 path2 26.4 33.1* -6.7 25.4 35.0* -9.6 0.354 0.241 0.187 mslew1 177.3 165.7 11.6 174.3 163.6 10.7 0.744 0.699 0.953 mslew2 171.7 179.4 -7.7 184.0 199.5 -15.5 0.473 0.193 0.733 slew1 97.6 118.2* -20.6 102.3 113.9 -11.6 0.244 0.648 0.438 slew2 112.3 131.6 -19.3 124.8 142.2 -17.5 0.295 0.407 0.918 aplhf 1.3 1.3 -0.1 1.3 1.4 -0.1 0.852 0.524 0.453 p1area1 2517.4 1109.5* 1407.9 2380.1 1137.7* 1242.4 0.321 0.496 0.246 p2area1 1346.8 765.9* 580.9 1474.8 778.6* 696.2 0.237 0.834 0.210 aspect11 33.9 46.0* -12.1 38.2 44.4 -6.2 0.068 0.651 0.191 aspect21 35.6 39.8 -4.3 38.2 44.3 -6.1 0.477 0.315 0.763 uslope11 88.5 110.1* -21.6 98.2 106.8 -8.6 0.133 0.716 0.272 uslope21 92.3 97.4 -5.1 100.7 107.9 -7.2 0.347 0.416 0.901 dslope11 58.1 80.2* -22.1 62.8 79.0* -16.2 0.773 0.82 0.573 dslope21 56.1 59.5 -3.5 57.6 67.3 -9.7 0.394 0.154 0.550 w11 11.8 6.9* 4.8 10.9 7.4* 3.5 0.103 0.18 0.045 w21 8.8 6.5* 2.3 8.7 6.1* 2.6 0.817 0.662 0.966 h11 386.2 299.7* 86.4 396.3 305.5* 90.8 0.632 0.653 0.767 h21 289.0 224.4* 64.6 307.0 244.9* 62.0 0.351 0.200 0.899 path11 29.0 45.8* -16.7 30.6 46.8* -16.2 0.317 0.699 0.890 path21 36.6 43.3* -6.8 33.9 45.8* -11.9 0.148 0.348 0.105 KC-score 1.2 0.6* 0.6 1.3 0.6* 0.7 0.284 0.491 0.657 Table 1. Waveform parameters including keratoconus score (KC-score) from the Ocular Response Analyzer for 34 patients treated with ReLEX FLEX in one eye and ReLEx SMILE in the other.   * indicates p<0.05 when pre-operative values and 6 months post-operative values are compared.                    

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Corneal biomechanical change assessment using biomechanical waveform analyzer parameters:Contralateral comparison of eyes having femtosecond lenticule extraction and small-incision lenticule extraction for moderate to high myopia

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