1

ARTICLE

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From CharlesCalifornia, US

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Presented in

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Q 2018 ASCPublished by

Efficacy and safety of a new selectivelaser device to create anterior

capsulotomies in cataract patientsPavel Stodulka, MD, PhD, FEBOS-CR, Richard Packard, MD, FRCS, FRCOphth, David Mordaunt, PhD

Purpose: To compare the efficacy and safety of anterior capsulot-omy creation with a new selective laser device (CAPSULaser) withthose of manual capsulotomies.

Setting: GEMINI Eye Clinic, Zlin, Czech Republic.

Design: Prospective case series.

Methods: Patients were placed in cohorts based on age andcataract grade and randomly allocated to have laser capsuloto-my or manual continuous curvilinear capsulorhexis (CCC). Theanterior capsule was stained with microfiltered trypan blue0.4%. The anterior capsulotomy was created with the laser de-vice focused on the anterior capsule through a custom patientinterface lens. Intraoperative video analysis with the use of anintraocular ruler and postoperative examinations were used toassess safety and efficacy (accuracy of capsulotomy size, circu-larity, centration).

ecember 22, 2017 | Final revision submitted: November 29, 2018 | Acc

University (Stodulka), Prague, Czech Republic; Arnott Eye Associates (PA.

EXCEL-LENS, Inc., Los Gatos California USA.

part at the ASCRS�ASOA Annual Meeting, Washington, DC, USA, April

g author: Richard Packard, MD, FRCS, FRCOphth, Arnott Eye Associate.

RS and ESCRSElsevier Inc.

Results: No intraoperative complications occurred in the laser groupor the manual group. All capsulotomies in the laser group were free-floating with no tags or tears. The mean capsulotomy diameter was5.03 mm overall (range 4.8 to 5.2 mm, laser group; 4.4 to 5.8 mm,manual group). In the laser group, all the capsulotomies were within0.1 mm G 0.1 (SD) of the target. The circularity accuracy wasgreater than 99.0% G 1.0%; the mean centration of thecapsulotomy in relation to the intraocular lens (IOL) was0.1 G 0.1 mm. All parameters were statistically significant (P < .01).The IOL–capsulotomy overlap was 360 degrees in all laser cases.

Conclusions: Selective laser capsulotomy using a new proprie-tary trypan blue formulation was safe and effective in cataract sur-gery. The sizing, circularity, and centration of the laser capsulotomywere more accurate than those of the manual CCC, resulting inconsistent 360-degree IOL coverage.

J Cataract Refract Surg 2018; -:-–- Q 2018 ASCRS and ESCRS

Online Video

Since the 18th century when Jacques Daviel first per-formed extracapsular cataract surgery,1 the openingof the anterior capsule has been an inherent and in-

tegral part of the procedure. Techniques for capsulotomyhave progressed from a crude tear to the current standardof continuous curvilinear capsulorhexis (CCC).2,3 In 2008,a new automated capsulotomy procedure was performedusing the femtosecond laser.4 For the first time, surgeonswere able to create anterior capsulotomies that weremore accurately sized, consistently round, and bettercentered than manually created capsulotomies. A capsu-lotomy of accurate size, shape, and position helps ensure360-degree overlap of the intraocular lens (IOL) by thecapsulotomy. This reduces the risk for posterior capsuleopacification5–7 and improves IOL centration and the

effective lens position.8 This is particularly importantwhen multifocal and toric IOLs are implanted.9,10 Howev-er, femtosecond laser–assisted cataract surgery has associ-ated caveats; that is, it requires a considerable investmentin capital and operating and maintenance costs.11

This study assessed the efficacy and safety of a capsulot-omy technique performed using the CAPSULaser selectivecapsulotomy laser (EXCEL-LENS, Inc.). We compared theresults with those of manual CCCs.

PATIENTS AND METHODSThis prospective controlled interventional case series study was anopen prospective, controlled, interventional case series. Surgerywas performed by 2 surgeons, one of whom was an author(PS), between August and December 2016 at Gemini Clinic,

epted: December 10, 2018

ackard), London, United Kingdom; EXCEL-LENS, Inc. (Mordaunt), Los Gatos,

2018.

s, 25 Queen Anne St, London W1G 9HT, United Kingdom. Email: eyequack@

0886-3350/$ - see frontmatterhttps://doi.org/10.1016/j.jcrs.2018.12.012

Figure 1. Selective laser device (inside red oval) attached to theoperating microscope. A safety filter for the surgeon’s eye is placedin the microscope stack.

Figure 2. Patient interface lens in place on the cornea of a patienthaving capsulotomy. The laser beam has already completed 270of the 360 degrees of the treatment.

2 SELECTIVE LASER DEVICE FOR ANTERIOR CAPSULOTOMIES

Zlin, Czech Republic. The protocol of the study was approved bythe local ethics committee and the national regulatory authority(Czech State Institute for Drug Control). The clinical investigationbegan after all relevant ethics committee and regulatory authorityapprovals (study reference 16EL01) were obtained. Writteninformed consent was obtained from each patient according tothe tenets of the Declaration of Helsinki.Patients were placed into cohorts based on age and cataract

grade and then randomly allocated to have a selective laser capsu-lotomy (laser group) or a CCC (manual group) using a stratifiedtechnique.12 Stratified randomization is a 2-stage procedure inwhich patients who enter a clinical trial are first grouped intostrata according to clinical features that may influence outcomerisk. Within each stratum, patients are then assigned to a treat-ment according to separate randomization schedules. The goalwas to create homogeneous randomized populations for higherstatistical accuracy for comparisons of potential surgical complica-tions and non-inferiority.13

Inclusion criteria were a clinically documented diagnosis ofgrade I to IV cataract according to the LensOpacities ClassificationSystem III,14 clear corneal media with no corneal disease or pathol-ogy that might interfere with passage of the laser light, age 40 to79 years, and an endothelial cell count of more than 2000 cells/mm2. To be included, patients must have read, understood, andsigned the informed consent and agree to be randomized to eithertreatment group. Standard exclusion criteria were used andincluded previous eye surgery, ocular comorbidities, and poorlydilating pupils. The study protocol stipulated 4 investigationalvisits to ensure that the patients fulfilled the eligibility criteria.

Selective LaserThe CAPSULaser unit attaches to the underside of the optics of astandard operating microscope using the mounting location for

Table 1. Preoperative patient characteristics by group.

Parameter

Group

Laser Manual

Patients (n) 63 62

Sex (n)

Male 35 37

Female 28 25

Age (y)

Mean 61.8 62.2

Range 42, 79 42, 79

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the Binocular Indirect Ophthalmomicroscope (BIOM, OCULUSSurgical, Inc.) (Figure 1). It is located so that the fixation light iscoaxial with the ocular view of the surgeon.The mechanism of action is selective laser absorption by a try-

pan blue–dyed anterior capsule. The wavelength of the laser is inthe red–orange range of the spectrum and absorbs trypan blueapplied to the anterior capsule. If the dye were not present, thelaser light would pass through the capsule without interactingwith it and rapidly extend to a large diffuse area on the retina.The dye absorbs the laser energy, providing localized heating ofthe capsule. This results in a phase change of the anterior collagenfrom type IV to amorphous. The laser is programmed to inscribe acircle; the collagen phase change allows the formation of a roll atthe capsulotomy edge, which increases its elasticity, as shown byin vitro studies.A Preclinical surgical testing on pig eyes andcadaver eyes combined with thermocouple measurements and his-topathology have shown that selective laser capsulotomy has anexcellent ocular safety profile.A The laser is compliant with therelevant safety standards for use in ophthalmic surgery.15–17

Preoperative AssessmentPreoperative examinations included uncorrected distance visualacuity (UDVA), corrected distance visual acuity (CDVA), auto-mated and manifest refractions, anterior segment slitlamp evalua-tion, specular microscopy, intraocular pressure (IOP), opticalbiometry (IOLMaster, Carl Zeiss Meditec AG), fundus slitlampevaluation, and optical coherence tomography.

Surgical TechniqueSelective Laser CapsulotomyA lid speculum was inserted and hy-droxypropyl methylcellulose placed on the cornea. A paracentesiswas created. Next, an air bubble was injected followed administra-tion of a new proprietary trypan blue formulation (CAPSULBlue,EXCEL-LENS, Inc.). The dye was left for 15 seconds and thenwashed out with a balanced salt solution. The chamber was filledwith sodium hyaluronate 2.0% using a back-fill technique. Hy-droxypropyl methylcellulose was again placed on the cornea,and the patient interface lens was positioned. The aiming beamof the laser was turned on and focused using the guide from theaiming beam. The fixation light was coaxial with the surgeon’sview, allowing most patients to fixate on the visual axis. Nextthe surgeon assessed centration and determined the location ofthe capsulotomy. The laser footswitch was depressed, which acti-vated the laser to fire with 1 continuous beam (versus multiplepulses) for 1 second to create the capsulotomy (Figure 2) (Video1, available at http://jcrsjournal.org). The capsulotomy disk wasremoved with a forceps, and the remainder of the cataract

Table 2. Preoperative age range distribution by cataract grade and group.

Grade 1 Grade 2 Grade 3

Age (Y) Laser Manual Laser Manual Laser Manual

70–79 4 4 7 7 5 5

60–69 5 5 12 12 3 3

50–59 10 10 7 7 0 0

40–49 4 3 5 5 0 0

3SELECTIVE LASER DEVICE FOR ANTERIOR CAPSULOTOMIES

surgery proceeded in typical fashion. All study-relevant laser set-tings were recorded.Continuous Curvilinear Capsulorhexis A standard CCC was

created using a forceps under an ophthalmic viscosurgical device.Once the disk was removed with the forceps, the remainder of thecataract surgery proceeded as normal.

Postoperative AssessmentFollow-up visits were performed at 1 week and 1 month andincluded the following: UDVA, CDVA, automated and manifestrefractions, slitlamp evaluation, IOP, and fundus evaluation by op-tical coherence tomography. In addition, specular microscopy wasrepeated 1 month postoperatively.Efficacy and safety were assessed based on video recordings dur-

ing the surgery as well as postoperative examinations findings.Adverse events and all observations were documented in elec-tronic case report forms. An external research organization per-formed site monitoring and controlled, verified, and analyzedthe electronic case report forms. The full dataset was used for allreported results.

Study EndpointsThe following study endpoints were assessed: adverse eventsrelated to the treatment procedures, determined intraoperativelyand 1 week and 1 month postoperatively; surgical efficacy of thenew trypan blue formulation as an intraocular dye for stainingthe anterior capsule; efficacy of the selective laser in anterior cap-sulotomy creation; and assessment of mechanical attachments(tags or bridges) between the disk and the capsulotomy rim aswell as anterior tears.Other endpoints concerned efficacy and comprised the accu-

racy of the capsulotomy diameter size, circularity, and centrationrelative to the IOL. All measurable parameters and the analysis ofthese measurements were assessed by independent reviewers.The accuracy of the capsulotomy diameter, defined as the abso-

lute value of measured diameter subtracted from the intendedtarget of 5.0mm, wasmeasured at the capsule plane using an intra-ocular ruler after the capsulotomy disk had been removed andbefore phacoemulsification. Videorecording frames that showedthe capsulotomy edge and intraocular ruler were selected andanalyzed for each capsulotomy. The image was calibrated with

Table 3. Preoperative and postoperative IOP by group.

Laser Group

Preop (n Z 63)

Postop

Value 1 Wk (n Z 62) 1 Mo (n Z 61)

Mean 16.3 15.1 14.6

SD 2.8 3.1 2.7

Median 16.0 15.0 14.5

Min 10.0 9.0 9.5

Max 25.0 24.0 20.0

the ruler placed in the capsule plane during surgery. The capsulot-omy rim edge was defined by the reviewer, who identified at least40 points. The least-squares method was used to determine thebest-fit circle (ie, circle diameter and center) for these identifica-tion points.To be consistent with previous literature,18–21 circularity was as-

sessed using 2 methods. First, it was calculated as follows:4p � area/perimeter2. Second, the least-squares approach wasused to determine the best-fit for an ellipse to the identified points,with the reported circularity value being the ratio of the major tominor axes. In both methods, a reading of 100% circularity repre-sented a perfect circle.A second video frame that clearly showed the capsulotomy edge

and the outside diameter of the IOL optic was selected. The cap-sulotomy rim and the IOL perimeters were defined by thereviewer, who identified at least 40 points for each. This imagewas calibrated with the outside diameter of the IOL. The least-squares method was used to determine the best-fit circle for thecapsulotomy and IOL outside diameter, determining that thebest fit was the centration difference between the IOL and thecapsulotomy.

Statistical AnalysisCONSORT guidelines22,23 were used to determine non-inferiorityand superiority. Using SAS software (version 9.4, SAS Institute,Inc.), an outside biostatistician calculated a minimum samplesize in each study group of 55 patients to achieve statistical confi-dence of at least 95% for non-inferiority, an assumed margin ofnon-inferiority of 0.05 mm, a test power of 0.8, and a dropoutrate of less than 10%. If non-inferiority was determined for selec-tive laser capsulotomy, superiority was tested.

RESULTSThree patients did not complete the study. Two patientsfailed to appear for postoperative visits in the study time-frame despite receiving reminders. One patient died fromcardiac disease not related to the surgery. Table 1 showsthe characteristics of the enrolled patients in the laser groupand manual group. The sex and age of the patients wassimilar in the 2 groups.

Manual Group

Preop (n Z 62)

Postop

1 Wk (n Z 61) 1 Mo (n Z 61)

16.1 15.0 14.9

2.8 3.0 2.7

16.0 15.0 14.5

9.5 9.0 9.5

24.0 22.5 22.5

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Figure 3. Distribution of cumulative CDVA in laser group (red data-points) andmanual group (blue datapoints). The solid lines representthe 1-month postoperative data, and the dashed lines represent thepreoperative data (CDVA Z corrected distance visual acuity;logMAR Z logarithm of the minimum angle of resolution).

4 SELECTIVE LASER DEVICE FOR ANTERIOR CAPSULOTOMIES

Table 2 shows the patient distribution by age range andcataract grade in both groups. The only between-group dif-ferences was the number of patients in the 40- to 49-yearage range with grade I cataract; 1 of the patients in this cate-gory was not eligible based on the exclusion criteria and wasremoved from the study.

SafetyThere were no capsulotomyor cataract surgery–relatedadverse events. No eye had flare, epithelial staining orerosion, abnormal iris changes, a malpositioned IOL, cys-toid macular edema, or other abnormal signs.Table 3 shows thepreoperative andpostoperative IOP; there

were no significant differences in IOP values or the postoper-ative decrease in IOP between the laser group and the manualgroup. Statistical analysis of the change in IOP from preoper-atively to 1-month postoperatively showed non-inferiority ofselective laser capsulotomy compared with CCC, with anon-inferiority margin of 1.0 mm Hg (P! .05).Figure 3 shows the preoperative and 1-month postopera-

tive cumulative CDVA data. The trend was similar betweenthe laser group and manual group, with no statistically sig-nificant differences. Themean improvement in CDVA from

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preoperatively to 1 month postoperatively was �0.3 loga-rithm of the minimum angle of resolution G 0.1 (SD) inboth groups. This shows the non-inferiority of selective lasercapsulotomy compared with CCC, with a non-inferioritymargin of 0.1 logMAR (P ! .05).The mean endothelial cell loss between preoperatively

and 1-month postoperatively was 11% G 5% in the lasergroup and 10% G 6% in the manual group. This showsthe non-inferiority of selective laser capsulotomy comparedwith CCC, with a non-inferiority margin of 2% (P ! .05).

EfficacyIn the laser group, all anterior capsules were uniformlystained to an intense blue with a single application of thetrypan blue. All capsulotomies in this group were free-floating with no mechanical attachments (tags or bridges)between the disk and the capsulotomy rim. No anterioror posterior tears occurred.Capsulotomy Diameter Figure 4 shows the difference in

capsulotomy diameters between the laser group and themanual group. The means were close to the intended diam-eter of 5.0 mm in both groups. However, the precision of thedistribution was greater in the laser group than in themanual group, with a standard deviation of 0.09 mm and0.31 mm, respectively. The diameter was withinG0.1 mm of the target in 54 cases (86%) in the laser groupand in 27 cases (44%) in the manual group. The capsuloto-my diameter was withinG0.4 mm in the range from 4.8 to5.2 mm in the laser group and withinG1.4 mm in the rangefrom 4.4 to 5.8 mm in the manual group.Figure 5 shows the frequency versus the diameter accu-

racy in both groups. The 99% confidence interval (CI)was 0.06 to 0.09 in the laser group and 0.17 to 0.30 mmin the manual group. Thus, the 99% CI for diameter accu-racy was 30 mm and 130 mm, respectively. The complete CIin the laser group was more favorable than the mean in themanual group, showing that the diameter accuracy in thelaser group was statistically significantly better (superior)than in manual group (P ! .01).Capsulotomy Circularity Compared with the least-

squares approach, the first method of calculating capsulot-omy circularity (4p � area/perimeter2) was more sensitive

Figure 4. Distribution of capsulot-omy diameters (5.0 mm intendedtarget) by group.

Figure 5. Frequency plots versusdiameter accuracy by group. The99% CIs are represented by hori-zontal lines with arrows. The blackline denotes the non-inferioritymargin, and all CIs to the rightof the line denote the region ofnon-inferiority (CI Z confidenceinterval).

5SELECTIVE LASER DEVICE FOR ANTERIOR CAPSULOTOMIES

to the smoothness of the edge and number of points used toidentify the edge but was relatively insensitive to the overallcapsulotomy shape. Both groups had a high degree of circu-larity (99.9% laser group; 98.5% manual group). The ratioof major axis to minor axis of the best-fit ellipse methodwas sensitive to the overall capsulotomy shape; thus, this ra-tio was used as the measure of circularity accuracy; themean was 99.2% in the laser group and 98.1% in the manualgroup.The distribution of circularity accuracy was close to the

target in both groups (Figure 6). 55 cases (88%) in the lasergroup and 21 cases (34%) in the manual group were within99% or more of circularity. The capsulotomy circularity ac-curacy (ratio of major to minor axes) in the laser group was97% or better; the circularity accuracy in the manual groupwas 94% or better.The 99% CI was 99.1% to 99.4% in the laser group and

97.7% to 98.4% in the manual group. The circularity accu-racy in the laser group was statistically significantly better(superior) than in the manual group (P ! .01).

Capsulotomy CentrationFigure 7 shows the capsulotomy centration relative to theIOL center. This could be measured only in approximately50% of cases in the manual group because the pupil was

smaller than the IOL optic and the IOL edge could notclearly be observed. Less miosis occurred and the pupilswere more dilated in the laser group, and centration wasmeasured in all patients. Centration of the capsulotomywas good in both groups, with all laser capsulotomiescentered less than 0.15 mm from the IOL center. In 3 casesin the manual group, the capsulotomy was more than0.4 mm from the IOL center, with the highest decentrationbeing 0.78 mm. The laser and manual groups are character-ized by a mean and 99% confidence interval of 0.06G 0.01and 0.10G 0.07mm, respectively. The centration accuracyin the laser group was statistically significantly better (supe-rior) than in the manual group (P ! .01).Figure 8 (left) shows ideal centration on the pupil and

IOL position, with complete 360-degree capsulotomycoverage of the IOL. In this case, the selective laser capsu-lotomy has a 5.0 mm diameter and 99.5% circularity andis decentered by 0.02 mm in relation to the IOL. Figure 8(right) shows major misalignment of capsulotomy in regardto the pupil and IOL center, with incomplete 360-degreecoverage. This example, an outlier in the manual group, ischaracterized by a 5.4 mm diameter, 97.2%, circularity,and 0.8 mm decentration from the IOL. The IOL is not intotal alignment with the pupil center, as seen by the hapticsthat center the IOL on the capsule bag equator, which is not

Figure 6. Capsulotomy circularityaccuracy by group. The horizontallines with arrows represent the99% confidence intervals.

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Figure 7. Deviation from centration by group. The horizontal lineswith arrows represent the 99% confidence intervals.

WHAT WAS KNOWN� Trypan blue can be used to stain the anterior capsulewithout adverse effects.

� Accurately sized capsulotomies covering the intraocular lens(IOL) edge lead to less posterior capsule opacification.

� Good centration is particularly important with advanced-technology IOLs.

WHAT THIS PAPER ADDS� The use of a new trypan blue dye to stain the anteriorcapsule used in conjunction with a new laser for capsulot-omies was safe and effective.

� The laser provided more accurate capsulotomy sizing,circularity, and centration than manually created continuouscurvilinear capsulotomies.

6 SELECTIVE LASER DEVICE FOR ANTERIOR CAPSULOTOMIES

circular. In all cases in the laser group and 56 cases (91%) inthe manual group, the capsulotomy edge covered the IOLfor 360 degrees.

DISCUSSIONIn recent years, technologies for creating more accuratecapsulotomies than obtained with the CCC method havebeen developed; these include the use of femtosecond la-sers4,19 and of precision pulse capsulotomy systems.24,25

The present clinical study determined that capsulotomydiameter, circularity, and centration were statisticallymore precise when selective laser capsulotomy was usedthan when manual CCC was performed. It also shows thevalue of homogeneous recruitment and randomized alloca-tion in better balancing baseline variables between a studygroup and a control group.The selective laser capsulotomy was safe, with no capsu-

lotomy- or cataract surgery–related adverse events. All cap-sulotomies in the laser group were free floating with nomechanical attachments (tags or bridges) between thedisk and capsulotomy rim. Furthermore, no anterior orposterior capsule tears occurred. Moreover, the clinical out-comes of the selective laser capsulotomy and CCC tech-niques were similar, with no statistically significantdifferences in the UDVA, CDVA, IOP, endothelial cellcount, or related slitlamp and optical coherence tomogra-phy examination findings. We recognize that the best wayto assess the endothelial cell count is in a contralateral studywith at least 3 months of follow-up, and we are planningsuch a study.The overall precision of the capsulotomy diameter size,

circularity, and centration was significantly better in thelaser group than in the manual group (P ! .01). We saw

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a trend indicating that increased precision of these 3 factorswould increase the rate of 360-degree coverage of the IOLby the capsulotomy. It has been shown clinically thatincomplete 360-degree coverage of the IOL by the capsulot-omy increases the likelihood of IOL tilting andmalposition-ing and the early-onset of posterior capsule opacification.5–7,18–21

Nagy et al.19 reported incomplete IOL coverage in 11% ofcases and 28% of cases in a femtosecond laser–assisted cata-ract surgery group and a CCC group, respectively. A 28%incomplete IOL coverage rate for CCC is high for modernuncomplicated cataract surgery. This implies a correlationbetween capsulotomy precision and 360-degree IOLcoverage. It also suggests that a precise capsulotomy diam-eter is not the only factor and that accuracy in circularityand centration are also important to achieving complete360-degree IOL coverage.Good centration on the visual axis is especially critical in

multifocal IOL and toric IOL implantation because smallamounts of decentration and tilt degrade image quality.Well-centered capsulotomies and IOLs might also lead tobetter predictability of the effective lens position8; however,this does not necessarily improve visual outcomes.26 Intra-ocular lens manufacturers are starting to produce IOLs thattake advantage of accurately sized and circular capsuloto-mies for capsulotomy capture of the IOL optic. The precisecentration of selective laser capsulotomies on the visual axiswill be important with these emerging designs.

Figure 8. Representative capsulotomies in laser group(left) and manual group (right). The gray dots representthe capsulotomy edge, and the blue circle representsthe best fit of the dots. The green circle representsthe outline of the IOL body, and the red circle denotesthe pupil center.

7SELECTIVE LASER DEVICE FOR ANTERIOR CAPSULOTOMIES

In conclusion, this 125-patient clinical study found thatselective laser capsulotomy and the new trypan blue formu-lation were safe and effective. No cataract surgery–relatedadverse events occurred. All laser capsulotomies were freefloating, and no anterior or posterior tears occurred.

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OTHER CITED MATERIALA. Daya SM, Packard R, Chee SP, Mordaunt DH. Pair-wise comparison of

manual, femtosecond-assisted laser, and selective laser capsulotomy tearstrengths (unpublished data)

Disclosures: Drs. Stodulka, Packard, and Mordaunt have a finan-cial interest in the product CAPSULaser and are equity shareholders inEXCEL-LENS, Inc.

First author:Pavel Stodulka, MD, PhD, FEBOS-CR

Charles University, Prague, CzechRepublic

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