ORIGINAL RESEARCH

Laboratory Investigation of Preclinical Visual-QualityMetrics and Halo-Size in Enhanced MonofocalIntraocular Lenses

Grzegorz Łabuz . Hyeck-Soo Son . Tadas Naujokaitis . Timur M. Yildirim .

Ramin Khoramnia . Gerd U. Auffarth

Received: September 6, 2021 / Accepted: October 8, 2021 / Published online: October 24, 2021� The Author(s) 2021

ABSTRACT

Introduction: This study aims to compare pre-clinical visual-quality metrics and halo size ofintraocular lenses (IOL) with enhanced inter-mediate vision to a standard monofocal lens.Methods: Three monofocal- IOL models withan extended-depth-of-focus (EDoF) intended formonocular implantation (Tecnis ICB00,AE2UV/ZOE, and IsoPure) and one for mono-vision (RayOne EMV) were compared against astandard monofocal lens (Tecnis ZCB00). Anoptical-metrology station was used in theassessment of IOLs’ optical quality in poly-chromatic light. The imaging quality was com-pared with metrics derived from the opticaltransfer function. Halo size was estimated fromthe projection of the point spread functionunder scotopic pupil.Results: The monofocal IOL showed the high-est image quality at the far focus. The ICB00’s,the AE2UV/ZOE’s, and the IsoPure’s

performance at - 1D was superior to that of themonofocal lens. The monocular defocus toler-ance of the RayOne EMV was comparable withthat of the ZCB00. The RayOne EMV’s inter-mediate range was improved in a monovisionconfiguration (- 1D offset). This approach,however, yielded the largest halo area, i.e., 53%of the ZCB00’s halo, compared to 34% for theIsoPure, 14% for the AE2UV/ZOE, and 8% forthe ICB00.Conclusion: The mono-EDoF models have aclear advantage over the standard monofocallens by expanded imaging capability beyond- 0.5D. Although the RayOne EMV providedthe largest (binocular) visual-range extension, itwas at the expense of monocular vision andhigher susceptibility to halo. The ICB00’s andthe AE2UV/ZOE’s halo-profile was similar tothat of the ZCB00, indicating their low poten-tial to induce photic phenomena.

Keywords: Enhanced monofocal; IOLs; Mono-EDoF; MTF; Photic phenomena; Preclinicalmetrics; PTF

Supplementary Information The online versioncontains supplementary material available at https://doi.org/10.1007/s40123-021-00411-9.

G. Łabuz � H.-S. Son � T. Naujokaitis �T. M. Yildirim � R. Khoramnia � G. U. Auffarth (&)The David J Apple Center for Vision Research,Department of Ophthalmology, University HospitalHeidelberg, Im Neuenheimer Feld 400, 69120Heidelberg, Germanye-mail: Gerd.Auffarth@med.uni-heidelberg.de

Ophthalmol Ther (2021) 10:1093–1104

https://doi.org/10.1007/s40123-021-00411-9

Key Summary Points

Why carry out this study?

A new category of intraocular lenses (IOLs)has been introduced that improvesintermediate vision of pseudophakicpatients and induces a comparable level ofphotic phenomena to a standardmonofocal implant. Given that those IOLsare of recent introduction, the scientificliterature on their performance is scarce.

Quality metrics derived from the opticaltransfer function offer a high correlationwith clinical visual acuity, which can beused to predict the clinical performance ofnew monofocal IOLs with an extendeddepth of focus prior to implantation.

What was learned from the study?

Enhanced-monofocal IOLs, based on ahigher-order aspheric design, provide acomparable far optical quality andextended intermediate range whileproducing a monofocal-lens halo type.However, the depth-of-focus extensionvaries between the models, which shouldbe taken into account in preoperativecounseling.

Although the enhanced-monovisionapproach offered an extended visualrange, a - 1D defocus and sphericalaberration effects might increase abinocular perception of photicphenomena.

INTRODUCTION

Monofocal intraocular lenses (IOLs) with anenhanced intermediate function can provide anextended range of vision with a far-dominantperformance, which, however, does not meetrequirements for extended-depth-of-focus(EDoF) lenses set by the American Academy of

Ophthalmology [1]. A recent clinical trialassessing mono-EDoF technology demonstratedthat patients with the Tecnis Eyhance ICB00have significantly better vision at intermediatedistances but similar at far compared to thosewith a standard Tecnis lens [2]. In anotherclinical investigation, higher spectacle inde-pendence was observed at the intermediaterange with the ICB00 compared to a monofocallens [3]. The performance of the ICB00 has alsobeen documented in laboratory studies [4, 5]. Inthose reports, however, only one IOL model hasbeen evaluated. But with increasing recognitionof this technology, various novel mono-EDoFlenses are being introduced, the precise char-acteristics of which have yet to be tested in thelaboratory before they become routinely used insurgery.

Objective metrics derived from in vitroassessment of IOLs are widely used to evaluatethe performance of new lens models [4–10] orfailed implants [11, 12]. One such metric is theoptical transfer function (OTF) that representsthe imaging ability of an optical system. This isa complex-valued function composed of themodulation transfer function (MTF) and thephase transfer function (PTF). The latestresearch indicates that optical-bench metricsoffer a high correlation with clinical measure-ments of visual acuity (VA) and contrast sensi-tivity (CS) [7–9]. The optical quality of IOLs istypically assessed, during their manufacture,using the through-focus MTF, which is theinternationally recognized standard for testingIOLs [6, 13]. However, the inclusion of the PTFcomponent may provide a more accurate esti-mate of the IOL’s performance and its impacton postoperative vision [14].

Halos are dim circles of light surrounding alight source, which may occur due to refraction,diffraction, or ray aberration. In the case ofIOLs, it often results from a simultaneous pro-jection of multiple foci by an IOL. Thus, thispostoperative complaint is typically associatedwith multifocal IOLs rather than monofocalones [15, 16]. Recent clinical and laboratorystudies demonstrated a comparable amount ofdysphotopsia with the ICB00 and the controlmonofocal Tecnis IOL [2–5], which may be usedas a reference to test the susceptibility of new

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mono-EDoF designs to produce suchphenomena.

This research aimed to apply the MTF andthe PTF to compare the optical quality and thehalo projection of the latest mono-EDoF modelsto that of a standard monofocal lens.

METHODS

Intraocular Lenses

In this laboratory investigation, we studied off-the-shelf IOLs; thus, ethics committee approvalwas not required. The following models wereassessed.

• Tecnis Eyhance ICB00 and Tecnis ZCB00(both from Johnson & Johnson SurgicalVision, Inc., Santa Ana, USA).

• AE2UV (Eyebright Medical Technology Inc,Beijing, China), distributed in Europe underthe tradename ZOE Primus-HD (OphthalmoPro GmbH, Sankt Ingbert, Germany).

• IsoPure 1.2.3 (PhysIOL sa/nv, Liege,Belgium).

• RayOne EMV (Rayner Intraocular LensesLimited, Worthing, UK).

Two IOL samples from each model weretested, each having the same refractive powerof ? 20D.

The Tecnis ZCB00 and ICB00 are made of thesame hydrophobic acrylic material with arefractive index of 1.47 at 35 �C and the Abbenumber of 55. The two models were designed tocorrect a spherical aberration (SA) of 0.27 lm at6 mm [17]. Despite a similar appearance, theEyhance’s anterior surface differs (by approxi-mately 15%) in its central, optical area fromthat of the ZCB00—having an increase in lenspower through utilizing higher-order asphericcomponents [4]. Thus, the Eyhance ICB00 aimsto enhance intermediate vision compared to theZCB00 while maintaining identical correctionof primary SA [4].

The AE2UV/ZOE is a hydrophobic-acryliclens with a refractive index of 1.47 and the Abbenumber of 57. The IOL features an asphericdesign to lower the primary SA of the cornea by- 0.20 lm at 6 mm. A high-order aspheric

surface enhances intermediate vision withincreased SA aberration in the IOL center thatgradually decreases towards the periphery. Asmooth and continuous higher-order asphericsurface aims to minimize photic phenomenathat may result from abrupt profile changes,such as observed in diffractive IOLs.

The IsoPure 1.2.3 is a hydrophobic-acrylicIOL with a refractive index of 1.52 and an Abbenumber of 42. The IsoPure features anterior andposterior aspheric surfaces with high-orderaspheric terms to extend the visual range com-pared to a monofocal IOL while maintaining agood far-focus performance. A posterior surfaceof the lens has a conic profile to correct- 0.11 lm of SA.

The RayOne EMV is made of (26%) hydro-philic-acrylic material with a refractive index of1.46 at 35 �C and an Abbe number of 56. TheRayOne EMV is offered as enhanced monovi-sion IOL where a plano target is maintained inthe dominant eye, and a power-offset is appliedin the non-dominant eye. According to themanufacturer, a 1D offset offers a 2.25D depth-of-focus extension in binocular vision. Theinner part of the IOL includes positive SA toimprove patients’ distance vision in the non-dominant eye.

Optical-Metrology Analysis

We used an OptiSpheric IOL PRO2 (TriopticsGmbH, Wedel, Germany) device in the assess-ment of the optical performance of the studyIOLs. This setup was built based on the ISOstandard configuration that includes a cornealmodel with 0.28 lm of SA at 5.15 mm [13]. Thedevice’s spectral property mimics the spectralsensitivity of the human eye with a peakintensity of 555 nm. The OTF components (i.e.,the MTF and the PTF) were derived from theline spread function projected by the devicethrough the tested IOL [18]. The longitudinalchromatic aberration of the model eye (withoutan IOL) was approximately 1D between 480 and644 nm [19]. We assessed the optical qualityparameters for the aperture size of 3 mm and4.5 mm at the IOL plane [20]. After finding thebest focus using the MTF criterion, the IOL’s

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tolerance to defocus was tested withina ? 0.50D to - 2.50D range (0.25-D resolution).At each focus-point, sagittal and tangentialMTFs and PTFs were acquired, and the twomeridians were averaged. Besides, at the 3-mmpupil, we recorded the 1951 USAF resolutiontest chart.

The weighted optical transfer function(wOTF) was calculated as described by Alarconet al. [7], who in a later study also applied thismetric to evaluate the optical quality of theICB00 lens [4]. The wOTF was derived from themeasured MTF and PTF at 3 mm and weightedby the neural CS function (CSF) using the fol-lowing formula:

wOTF ¼ d

150

X150d

f¼1MTF fdð Þcos PTF fdð Þð ÞCSF fdð Þneural;

where f is the spatial frequency expressed in lp/mm with a resolution of d = 1 lp/mm. Theneural CSF data were obtained from the work ofCampbell and Green [21]. The wOTFb changewith defocus (where b is - 0.36) has beenreported to correlate strongly with clinicallymeasured VA, and we compared this changebetween models [7, 22].

A polychromatic point spread function (PSF),i.e., an image of a 0.1-mm pinhole, was used toassess the size of halos projected by the IOLs atthe 4.5-mm aperture [4, 16]. A long transfor-mation of each recorded image was applied, andthe background noise was removed. The halosize was defined as the total area (2-D images)with the assumption of circularity.

Binocular Summation

Given that the RayOne EMV is implantedbilaterally through monovision, we performedthe binocular summation of recorded USAF-chart and PSF images. We applied a quadraticsummation proposed by Legge and Rubin for apair of images corresponding to the left andright eye with the defocus offset of 1D [23, 24].

Data Analysis

The analysis of optical-quality data and imageswere performed with custom-made softwaredeveloped in MATLAB (MathWorks, USA).

RESULTS

The MTF curves of all IOL samples measured atthe best focus through the 3- and 4.5-mmapertures are presented in Fig. 1 with 2D MTFvisualization shown in Fig. 1S (SupplementaryMaterial).

At 3 mm, the ZCB00 demonstrated thehighest MTF values of the five models, particu-larly at higher spatial frequencies, with anaverage level of 0.50 ± 0.00 at 50 lp/mm. TheAE2UV/ZOE produced the average MTF @ 50 lp/mm of 0.37 ± 0.02. At the same frequency, theICB00’s MTF was comparable, and that was0.36 ± 0.01. The RayOne EMV’s MTF was0.40 ± 0.00, which was reduced dramaticallyafter the 1D offset (MTF = 0.04 ± 0.01). TheIsoPure’s performance at 50 lp/mm (MTF =0.41 ± 0.01) was minimally better than found

in the other mono-EDoF models.At 4.5 mm, the ZCB00’s high-frequency per-

formance (MTF@50 lp/mm = 0.39 ± 0.01) wasbetter than that of the mono-EDoF IOLs. TheICB00’s MTF was 0.31 ± 0.01, comparable tothat measured with the AE2UV/ZOE(0.29 ± 0.00) at 50 lp/mm. For the IsoPure, itwas 0.23 ± 0.00. The RayOne EMV’s MTF atzero-defocus was 0.17 ± 0.00, but a simulationof a - 1D refractive target resulted in a poor far-focus performance at 4.5 mm (MTF@50 lp/mm = 0.02 ± 0.00).

Figure 2 reports the wOTFb change withdefocus for the five IOL models. The wOTFb ofthe ZCB00 was minimally better at the best far-focus than that of the other models. However,at about - 0.5D, the ICB00, the AE2UV/ZOE,and the IsoPure demonstrated improved toler-ance to defocus compared to the monofocalIOL. The RayOne EMV’s and the ZCB00’s per-formance under defocus was comparable withthe simulated plano refractive target. Althoughthe 1D offset resulted in a worse wOTFb level ofthe RayOne EMV at the far focus, in binocular

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vision, the defocus tolerance may be furtherextended.

The resolution-test images confirm thewOTFb results. Figure 3 presents the quadraticsummation results for the RayOne EMV and therecorded (single) images for the other models.Figure 2S (Supplementary Material) shows thecomparison between the USAF-

chart photographs taken with the simulatedplano and - 1D refractive target and the corre-sponding binocular image.

The PSF projection confirmed a similar haloprofile among the ZCB00, the ICB00, and theAE2UV/ZOE (Fig. 4). The ZCB00 produced thehalo radius of the smallest size (1.73 ± 0.06arcmin), which was closely followed by theICB00’s 1.88 ± 0.08 arcmin and AE2UV/ZOE’s2.01 ± 0.04 arcmin. The IsoPure created a halowith an average size of 2.64 ± 0.00 arcmin. TheRayOne EMV’s binocular halo size was3.67 ± 0.18 arcmin, which was the largestamong the studied IOLs. Figure 3S (Supple-mentary Material) shows the PSF images of theRayOne EMV at zero, and - 1D defocus with thecorresponding quadratic summation.

DISCUSSION

This study provides further evidence thatmono-EDoF IOLs have the potential to improvethe patient’s visual function at the intermediaterange while producing the optical performancethat is close to that of standard monofocal IOLsat their best focus. Although the RayOne EMVshowed a more extended range of vision thanthat of the other mono-EDoF models, theimpact of binocular summation is challengingto predict in a laboratory setting.

Fig. 2 Defocus tolerance of the weighted optical transferfunction to the power of b = - 0.36 (wOTFb) assessed at3 mm and visual acuity (VA) predictions presented on asecondary axis. The dotted lines show each lens0 valuesseparately; the solid lines refer to the average of twosamples. The vertical dashed line indicates the position ofthe far focus

Fig. 1 Modulation transfer function (MTF) levels of the studied IOLs at the best focus for 3- and 4.5-mm apertures. Thedotted lines show the values of each lens separately; the solid lines refer to the average of two samples

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Fig. 3 US Air Force resolution targets recorded at a defocus range of ? 0.5D to - 2.5D and the 3-mm aperture.*Quadratic summation of two images with the defocus difference of 1D

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Given that the studied IOLs are still relativelynew to clinicians, we were not able to identifyany peer-reviewed publication on the in vivo orin vitro functioning of the AE2UV/ZOE, Iso-Pure, and the RayOne EMV. This gap underlinesthe importance of our research. In a recentpublication, Mencucci et al. made a clinicalcomparison of the ZCB00 and ICB00 [3]. Vari-ous aspects of the visual function were assessed,including VA, CS, and the perception of photicphenomena. They found that monocular cor-rected distance VA differs only by 0.01 in favorof the ZCB00 group. However, monocular dis-tance corrected intermediate VA measured at66 cm (* 1.5D) was improved in patients withthe mono-EDoF lens by one line [3]. Thosefindings are in agreement with the results of ourin vitro evaluation, as we also found that ZCB00had a minimally higher wOTFb than the ICB00at far-point, but worse at intermediate by 0.12.Following the conversion of the wOTFb to log-MAR VA using a model proposed by Alarconet al. [7, 22], a 1.3 line difference between thetwo Tecnis IOLs can be predicted at - 1.5D.

In a paper by Auffarth et al., the Europeanmulticenter study results on the comparisonbetween the ICB00 and ZCB00 IOLs were pre-sented [2]. They found that the mean correcteddistance VA was - 0.02 ± 0.01 logMAR in themono-EDoF group and - 0.06 ± 0.01 logMARin the standard-monofocal one. In the currentin vitro study, we also found a minimallydecreased wOTFb of the ICB00 IOLs at the farfocus with the estimated VA effect of 0.02 log-MAR in favor of the ZCB00 group. At theintermediate range (66 cm), the distance cor-rected VA was 0.19 ± 0.02 logMAR and0.31 ± 0.02 logMAR in the mono-EDoF andmonofocal patients, respectively. They reportedthe mean improvement of 0.11 ± 0.02 logMAR,which is close to the predicted level from ourin vitro assessment. At 1.5D defocus, theAE2UV/ZOE’s wOTFb only slightly differed fromthat of the ICB00, which would result in aminimally lower VA by 0.01 logMAR and 0.03logMAR at 2.5D according to the model [7, 22].The AE2UV/ZOE provides a clear advantageover the standard monofocal lens, as at 66 cmand 40 cm, one line VA improvement (0.1 log-MAR) is expected at both distances compared to

the ZCB00. For the IsoPure it is less, about 0.07logMAR at 1.5D of defocus. Although RayOneEMV showed\0.02 logMAR difference over themonofocal lens in the ‘dominant eye’ simula-tion, in the ‘non-dominant eye’ a nearly 3-line(0.27 logMAR) improvement would be expec-ted. However, these laboratory results should beconfirmed in a clinical study.

The ICB00 and the ZCB00 have also beencompared in a laboratory setting. Alarcon et al.studied their optical quality by measuring theMTF and the OTF in polychromatic light usingtheir optical bench [4]. Despite expected differ-ences in our and the J&J Vision group’s opticalsetup, they also predicted a 0.12 logMARimprovement at the intermediate range afterthe implantation of their mono-EDoF lenscompared to the standard monofocal model.Furthermore, Alarcon and associates reported anegligible impact of higher-order aberrationsand pupil size on their comparison. However,Vega et al. found a shift of the through-focusMTF area by - 0.50D at 2 mm, indicating somelevel of pupil dependency [5]. Although Auf-farth et al. did not see clinically significantchanges for pupils larger than 2.5 mm [2], thecomparison for smaller pupils was not per-formed due to insufficient sample size. Moreresearch is needed to determine the impact ofpupil size on the visual quality of patients withthe new mono-EDoF IOLs.

The European multicenter clinical studyconcluded that the occurrence of photic phe-nomena is comparable between the ICB00 andZCB00 IOLs [2]. Mencucci et al. also reportedinsignificant differences between the twogroups in the perception of glare and halo [3].The two laboratory studies have shown that theICB00 and the ZCB00 produce a similar halopattern with a slightly lower intensity profile forthe latter model [4, 5]. Our analysis of the PSFmay further reinforce those findings, as we alsoreported that the observed halo was only 8%larger in the ICB00 than that recorded throughthe monofocal lens. This difference was slightlyincreased but still comparable for the AE2UV/ZOE, which was 14%. Our results indicate thatthe AE2UV/ZOE’s contribution to photic phe-nomena is minimal, and it is comparable to thatof a monofocal lens.

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The IsoPure and the RayOne EMV produceda halo pattern that was larger than that of theZCB00 by 34% and 53%, respectively. Onepotential explanation of this observation is alower SA correction. In the current study, thecornea model exerts 0.28 lm of SA while theIsoPure corrects - 0.11 lm, but the RayOneEMV is considered ‘aberration neutral.’Although the choice of this SA correction mighthave been motivated by the broad range of SAdistribution in the population, in this in vitromodel, we simulated the average SA value of thecornea [17], which favors the lens design of theTecnis IOLs. In such a setting, however, theIsoPure and RayOne EMV performance at thescotopic pupil could be compromised, whichmight also result in an increased halo-patterndue to a higher level of SA. Two other factorsmay also contribute to the increased halo size inthe RayOne EMV.

1. The Rayner model induces additional pos-itive SA to optimize the far vision of thenon-dominant eye. Thus, we expect thatincreased SA effects may spread the RayOneEMV’s halo-profile and reduce the opticalquality, as shown in Fig. 1.

2. Similarly, defocus blur also has the poten-tial to increase the halo perception [25, 26].

Figure 4 shows the quadratic summation ofthe focus and unfocused (1D offset) PSF.Although both log images (Fig. 3S, Supplemen-tary Material) show an extended halo patternaround the central disk, defocus appears toproduce higher-intensity effects in the simula-tion of the 1-D offset. Johannsdottir and Stel-mach found that subjective complaints aboutphotic phenomena under low-light conditionsare more common in monovision compared tobinocular emmetropia [25]. Still, the monovi-sion approach provides fewer halo symptomsthan the implantation of a diffractive-bifocal

IOL, as Zhang et al. have demonstrated [26].Thus, whether the observed increased haloprofile in the RayOne EMV may induce func-tionally significant photic phenomena is aquestion that must be addressed in a clinicalstudy.

In a healthy emmetropic eye, the summationof the visual information from both eyes resultsin enhanced visual perception compared tomonocular vision. Campbell and Green esti-mated that binocular summation improves the

visual quality by a factor offfiffiffi2

p[27]. However, a

recent meta-analysis by Baker and Lygo indi-cates that the ratio between binocular andmonocular perception may be higher, implyinga multifactorial mechanism underlying thisprocess [28]. Conversely, the binocular sum-mation may also be hampered, e.g., undermonovision correction, with the ratio close toor less than 1 indicating the deterioration ofbinocular vision [29, 30]. If we assume that thebinocular summation is 1 for the RayOne EMV

andffiffiffi2

pfor other IOLs, the far-focus wOTFb

increases for all models but one (Fig. 5). Thebinocular summation may also minimize theimage quality difference between the RayOneEMV and the other mono-EDoF models at theintermediate distance, which may be a good

bFig. 4 Logarithmic images of the recorded polychromaticpoint spread function (PSF, left panels) at 4.5 mm withcolor-coding. The right panels present the linear cross-section of the PSF’s intensity profile. *Quadratic summa-tion of two images with the defocus difference of 1D

Fig. 5 Simulations of wOTFb binocular summation at3 mm and under defocus. The dotted lines show each lens0

values separately; the solid lines refer to the average of twosamples. The vertical dashed line indicates the position ofthe far focus

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option for patients who may not tolerate welldissimilarity in the blur perception between theeyes. More research is needed to determine theimpact of enhanced monovision on patients’binocular performance.

The use of one pupil size (i.e., 3 mm) mightnot fully represent a clinical situation [23],which may be considered a limitation of thecurrent study. However, the wOTF metric wascomputed by Alarcon et al. from laboratory dataobtained at 3 mm [7]; thus, its implementationfor other pupil sizes requires validation. Thisshould be a subject of further research.

CONCLUSIONS

We found that the mono-EDoF models’ far-point MTF was minimally lower than that of thestandard monofocal IOL, but the expectedimpact on clinical VA is negligible. All mono-EDoF models have the potential to extend thepatient’s intermediate vision beyond the rangeof a standard monofocal lens. Our laboratoryresults for the two Tecnis IOLs appear to con-form to the published results from otherresearchers. We found that the AE2UV/ZOE andthe ICB00 produced a halo pattern comparableto that of the ZCB00 indicating a low potentialof these IOLs to induce photic phenomena.

ACKNOWLEDGEMENTS

Donald J. Munro contributed to the review ofthe manuscript. Ethics committee approval wasnot required for this laboratory study.

Funding. This work was supported by unre-stricted research grants from Klaus Tschira Stif-tung and Eyebright Medical Technology Co.,Ltd. The sponsors had no role in the design,execution, interpretation, or writing of thestudy. T. M. Yildirim is funded by the Physician-Scientist Program of the Heidelberg University,Faculty of Medicine, Heidelberg, Germany.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for this

article, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Authorship Contributions. Conceptualiza-tion, GŁ and GUA; methodology, GŁ; investi-gation, GŁ, H-SS, TN, TMY, RK and GUA; dataanalysis, GŁ, H-SS, TN, and TMY; resources,GUA and RK; draft preparation, GŁ and H-SS;review and editing, GŁ, H-SS, TN, TMY, RK andGUA; supervision, GŁ, RK and GUA; projectadministration, GUA; funding acquisition,GUA. All authors have read and agreed to thepublished version of the manuscript.

Disclosures. Gerd Uwe Auffarth reportsgrants, personal fees, non-financial support andconsulting fees from Johnson & Johnson andAlcon, grants, personal fees, and non-financialsupport from Carl Zeiss Meditec, Hoya, Kowa,Oculentis/Teleon, Rayner, Santen, Sifi, Ursa-pharm, grants and personal fees from Biotech,Oculus, EyeYon grants from Acufocus, Conta-mac, Glaukos, Physiol, Rheacell, outside thesubmitted work. Ramin Khoramnia reportsgrants, personal fees, and non-financial supportfrom Alcon, Johnson&Johnson, Hoya, Physiol,Rayner, personal fees, and non-financial sup-port from Kowa, Ophtec, Oculentis/Teleon,Santen, and Acufocus, outside the submittedwork. Grzegorz Łabuz, Hyek-Soo Son, TadasNaujokaitis, and Timur M. Yildirim have noth-ing to disclose.

Data Availability. The datasets generatedduring and/or analyzed during the currentstudy are available from the correspondingauthor on reasonable request.

Open Access. This article is licensed under aCreative Commons Attribution-NonCommer-cial 4.0 International License, which permitsany non-commercial use, sharing, adaptation,distribution and reproduction in any mediumor format, as long as you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons licence, andindicate if changes were made. The images orother third party material in this article areincluded in the article’s Creative Commons

1102 Ophthalmol Ther (2021) 10:1093–1104

licence, unless indicated otherwise in a creditline to the material. If material is not includedin the article’s Creative Commons licence andyour intended use is not permitted by statutoryregulation or exceeds the permitted use, youwill need to obtain permission directly from thecopyright holder. To view a copy of this licence,visit http://creativecommons.org/licenses/by-nc/4.0/.

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