Cheryl Guttmanin Lisbon

ONCE a subject of scientific curiosity,corneal biomechanics is now the focus ofintense research in many areas of clinicalophthalmology.A special symposium of theJournal of Cataract and Refractive Surgeryheld during the XXIII Congress of theESCRS spotlighted the most recentdevelopments.

Cynthia Roberts PhD,The Ohio StateUniversity, chairperson of the symposium,explained that with increasedunderstanding of corneal biomechanicscomes the potential to identify sources oferror in IOP measurement and thereforeto develop more accurate tonometrytechniques.A better understanding ofcorneal biomechanics might also allow forimproved predictability of refractivesurgery outcomes and could improve thepreoperative identification of eyes at riskfor developing ectasia after refractivesurgery.

“Corneal biomechanics can be exploitedto manipulate shape and vision, and I seebiomechanical customisation as the nextgeneration in refractive surgery,” DrRoberts said.

She cited various studies to show thatthe corneal biomechanical response can bemanipulated once it is understood. Forexample, a study by John Marshall PhD,showed refractive predictability afterLASIK could be improved by changingfrom a 5.0 mm to a 6.0 mm optical zone.The explanation for the differences lies incorneal biomechanics.

“Adding 1.00 mm to the ablation zonewipes out some of the peripheral lamellar

segments that aredrivers to thebiomechanicalresponse and doingthat reduces thevariability associatedwith variation inbiomechanicalproperties,” noted DrRoberts.

In addition, acontralateral eye studyperformed by DrRoberts andcolleaguesdemonstrated thebiomechanicalresponse after LASIKcould be manipulatedby the choice of laserused to perform theablation.The effect wasmeasured bydifferences in inducedhigher orderaberrations and couldbe attributed tobetween-laserdifferences in ablationzone sizes.

Modelling based onstructuralcharacterisationWilliam J. Dupps MD,PhD, first described abiomechanical modelof corneal response tosurgery in 1995.According to thatmodel, the normalcornea is seen as astacked layer oflamellae and can beanalogised to rubberbands with sponges inbetween.A refractivesurgery procedure thatcircumferentially seversthe tension-bearinglamellae can bethought of as removingtension from some ofthe rubber bands.As aresult, they can nolonger hold water outof the sponges, and inthe midperiphery andperiphery, the spongesswell.

In the eye, that change is seen asparacentral and peripheral thickening andsteepening. However, due to structuralinterconnections and communicationbetween anterior and posterior layerswithin the cornea, any procedure thatcircumferentially severs tension-bearinglamellae also leads to central biomechanicalflattening.

Biophysicist Keith Meek PhD, andcolleagues at Cardiff University have beenusing X-ray diffraction to analyse theultrastructure of the corneal stroma inorder to shed light on how the cornearesponds as a unit to a procedure thataffects only one part of it.

“Collagen provides mechanical strengthto the cornea and it is the orientation anddistribution of the fibrils that largely governhow the cornea responds to mechanicalstress.That is why it is important to studythe distribution and organisation of lamellaein the cornea,” Dr Meek said.

The technique being used involves passingan intense beam of x-rays, generated by asynchrotron, through the cornea andmeasuring how the x-rays are scattered.This provides unique quantitativeinformation about fibril orientation anddistribution and allows these parameters tobe mapped across the cornea.

At present, only two-dimensional mapsare produced.Whilst these can help toexplain some of the gross biomechanicalproperties of the cornea, Dr Meek notedthat a three-dimensional model would beneeded to determine potential implicationsfor refractive surgery.

Studies comparing normal eyes and thosewith keratoconus show that the grossorganisation of the stromal lamellae isdramatically disturbed in the keratoconiceyes compared with the normal eyes,particularly in the cone position. In addition,there is variation in the distribution of thecollagen fibrillar mass in the keratoconiceyes as compared with the relativelyuniform distribution seen in the normalcornea.

“These findings lend further support tothe concept that collagen organisation inthe cornea is pivotal to the shape of thistissue,” Dr Meek said.

New measurement tools Researching corneal biomechanics and theability to effectively manipulate thoseproperties in clinical practice will dependon the availability of tools that allow non-invasive, in vivo measurement.

Journal of Cataract and Refractive Surgery SymposiumCorneal Biomechanics

Lisbon 2005

Schematic diagram of the biomechanical response to circumferential severing of corneal lamellae.The anterior peripheral lamellar segments are “relaxed” allowing swelling which leads to central

flattening and peripheral steepening.

Schematic diagram of the proposed influence of ablation zone size on the biomechanical response.By ablating more of the peripheral lamellar segments, the biomechanical response is reduced, and

the variability due to individual biomechanical properties is reduced.

Average tangential curvature maps from a contralateral eye study indicating that the eyes with thesmaller ablation zone (right) had significantly greater paracentral steepening and also spherical

aberration induction, than the contralateral eyes.

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“Corneal biomechanicscan be exploited tomanipulate shape andvision, and I seebiomechanicalcustomisation as thenext generation inrefractive surgery,”

Cynthia Roberts PhD

“For years, no one but scientists in thefield cared about optical aberrations.However, with the development ofwavefront sensors and the ability tomeasure wavefront errors came newinterest and research that led tounderstanding of how to control thatoutcome,” Dr Roberts said.

William J. Dupps MD, PhD, Cole EyeInstitute, described two investigationalmodalities for measuring cornealbiomechanical properties.

The first is a handheld ultrasoundprototype device dubbed the Sonic Eye,which is being developed by PriaVision, Inc.It measures the “time of flight” or velocityof a wave propagated between two pointsalong a tissue sample.

“This instrument provides one modalityfor characterising corneal stiffness.Thepropagation speed of a sonic wave is fasterin a stiffer cornea,” Dr Dupps explained.

In testing a prototype device in porcineand human donor eyes, Dr Dupps andcolleagues found that the technology offersgood measurement repeatability across

different regions of the cornea, yieldsresults that are not confounded by theepithelium, and has a sampling depth rangethat lies somewhere between 250 and 750microns. It also performed as predicted inshowing an increase in wave velocityfollowing corneal cross-linking anddecreases in velocity after relaxingincisions.

“Issues that need to be addressed in theclinical setting include sensitivity to surfacehydration, IOP and indentation artefacts,”he added.

A second instrument that Dr Dupps iscreating with collaborators Matthew Fordand Andrew Rollins PhD from CaseWestern Reserve University is a non-contact system that uses high-speed OCTand sophisticated software to measure andmap both the magnitude and direction ofstrain within different layers of the cornea.

Currently, the information is depicted intwo formats: 1) as a two-dimensional,cross-sectional map using different coloursto represent different levels of strainintensity, and 2) as a vector map that

provides informationon strain directionand magnitude.Theresearchers arecurrently developingsoftware that willprovide a three-dimensionalreconstruction ofstrain within thecornea.

Among thepotential applicationsfor this technology,early detection ofkeratoconus may bemost important.Thelong list of otherpossible uses includescharacterisation ofwound healingresponses in post-keratoplasty eyes andthe prediction ofbiomechanicalresponses torefractive surgery.

“Ultimately,however, our toolboxfor investigatingcorneal biomechanicalproperties will needto contain a variety ofdifferent instruments,each providing adifferent view of thesecomplex phenomena.In addition, translationof this informationinto clinical use willrequiremultidisciplinary

collaboration to translate complexbiomechanical tissue data into improveddiagnostic criteria for ectasia and enhancedsurgical outcomes,” said Dr Dupps.

Characterising biomechanicalresponses to corneal proceduresSeveral speakers presented studiesinvestigating the effects of differentrefractive surgery procedures on thecornea’s biomechanical response. SunilShah MD,The Midland Eye Institute,Birmingham, UK, used the currentlymarketed Ocular Response Analyzer(ORA, Reichert) to measure changes incorneal hysteresis, which is a reflection ofcorneal viscoelasticity.

The study followeda consecutive seriesof 80 eyes thatunderwent LASIK orLASEK. Between-group differenceswere expected sinceLASIK places theablation deeper in thecornea where thelayers are structurallydistinct from themore superficiallayers.

The amount ofhysteresis wasreduced significantlyfrom 11.5 mm Hg(range 7.9 mmHg to16.7 mmHg) atbaseline to 9.3 mmHg (range 2.5 mmHgto 13.1 mmHg) forthe overall cohort.However, the meanchange in hysteresiswas not significantlydifferent between theLASIK and LASEKgroups.

“We weresurprised by thatfinding as we hadexpected cutting alamellar flap for

LASIK would affect the biomechanicalproperties of the cornea differently than aLASEK surface ablation,” Dr Shah said.

There were other important findings inthe study. For example, Dr Shah noted thatthe mean postoperative hysteresis value of9.3 mmHg is lower than the mean for thekeratoconus population at his clinic.

“This observation suggests thatrefractive surgeons probably do need tobe concerned about the biomechanicaleffects of their procedures on the cornea,”he commented.

In addition, a regression analysis of therelationship between change in cornealhysteresis and change in corneal thicknessshowed only a moderate correlation atbest due to very wide spread of the data.

“This finding indicates hysteresis doesnot change by a predictable amount perunit change in corneal thickness, and sorefractive surgeons cannot use cornealthickness change to predict which patientswill have a huge postoperative reduction inhysteresis and therefore biomechanicalproperty problems. However, it may beprudent to not offer refractive surgery toa patient with a low hysteresis or at leastto counsel that individual about potentialrisk,” Dr Shah said.

“Issues that need to beaddressed in theclinical setting includesensitivity to surfacehydration, IOP andindentation artefacts,”

William J. Dupps MD, PhD

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Map based on X-ray diffraction findings showing the orientation of preferentially aligned lamellae atdifferent points across the cornea superimposed on a picture of an eye. The cornea’s collagen isarranged predominantly vertically and horizontally in the central cornea whereas it is essentiallytangential at the edge of the cornea. As one moves from the centre of the cornea, there is more

collagen so the plots get larger. The map allows you to see at a glance if a given penetratingincision would sever the fibrils or cut parallel to most of them.

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Kieth MeekCynthia Roberts Jay Pepose Jesper Hjortdal Michael Knorz Ioannis Pallikaris

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Jesper Hjortdal MD and colleagues atAarhus University are also comparingoutcomes after surface ablation andintrastromal procedures to determinewhether the two surgeries arebiomechanically distinct.Their long-termstudy originally randomised 45 eyes withmyopia between -6.0 and -8.0 D to PRK orLASIK. Corneal rigidity was assessed by theapparent IOP value measured withpneumotonometry (Reichert).

The results showed the apparent IOPreadings were significantly affected after bothsurgeries, mainly due to the reductions incorneal thickness. For both groups, apparentIOP was approximately 6.0 to 7.0 mmHglower after the procedure, and that changecould be partly explained by the 70 to 80micron reductions in central cornealthickness (CCT) associated with theprocedures.

When the results were analysed with thedata divided by follow-up interval, time-dependent differences were noted. Betweenone and 12 months after surgery, there wasa large increase in CCT in the PRK eyes butlittle change in the LASIK group. However,apparent IOP increased significantly in theLASIK eyes. Between one and three yearsafter surgery CCT increased slightly and to asimilar extent in both groups, while apparentIOP increased slightly in the PRK eyes anddecreased slightly in the LASIK eyes.

“These data indicate corneal rigidity ispermanently decreased after both LASIK andPRK. However, there appears to be someinterlamellar healing during the first yearafter LASIK while over the long-term, somere-stiffening appears to occur in eyes thatundergo PRK,” Dr Hjortdal said.

Michael C. Knorz MD, FreeVis LASIKCentre, Mannheim, Germany, evaluated thetopographic and wavefront changesoccurring when LASIK was performed in atwo-step procedure in order to separatelycharacterise the cornea’s biomechanicalresponses to flap creation and ablation. Heobtained measurements from 48 eyes of 24patients after the flap was cut, lifted, andreplaced.Then, patients returned threemonths later for the ablation, and thetopographic and aberrometry measurementswere repeated.

The topographic evaluations showed theflap creation caused no change in centralcurvature, although cutting the cornea wasassociated with a significant increase inparacentral curvature and an even greaterincrease in peripheral curvature. Consistentwith the biomechanical response modelintroduced by Dr Dupps, the ablation causeda significant decrease in central curvature

and was also accompanied by a significantincrease in paracentral and peripheralcurvature.

Results from wavefront evaluation showedthe flap creation caused a significant increasein spherical aberration that was consistentwith the increase in peripheral steepening.Spherical aberration was also increasedsignificantly by the ablation, despite the factthat the procedures were customised.

“The results of this study show that bothcutting the flap and the laser ablationindependently cause an increase in peripheralcorneal curvature and thereby sphericalaberration, and these findings underline theimportance of understanding cornealbiomechanics in order to refine ablationpattern algorithms,” Dr Knorz said.

Implications for IOP measurementUnderstanding of corneal biomechanics andthe effects of refractive surgery on thoseproperties is also important for determiningglaucoma risk because some of the standard

assessment tests, including laser polarimetryand tonometry, are filtered through thebiomechanical properties of the cornea.

Research in the area of IOPmeasurement has revealed thatbiomechanical properties, rather thancorneal thickness or curvature, are likelythe largest source of error in IOPmeasured with Goldmann applanationtonometry (GAT).The Ocular responseAnalyzer (ORA, Reichert) and the PascalDynamic Contour Tonometer (PDCT, SMTSwiss Microtechnology) are two newcommercially available tonometryinstruments that may reduce errors due tothe biomechanical property changesinduced by laser ablation refractive surgery.

Jay Pepose MD PhD, Pepose VisionInstitute and Washington University Schoolof Medicine, reported the results of aprospective study comparing pre- to post-LASIK IOP changes measured using GAT,the ORA, and the PDCT in a cohort of 66eyes with an average MRSE of -5.0 D.Twovalues were generated with the ORA: theORA-G, which has been shown to correlatewith the GAT value, and an IOP-CC, whichis a corneal compensated measure,generated using a new third-generationnomogram.

There was a greater mean reduction inpost-LASIK IOP when it was measured withthe GAT and ORA-G than with PDCT.TheIOP reduction measured with the ORA wasminimised by the IOP-CC.The GAT andORA-G values were correlated topachymetry, while the IOP measurementderived with the PDCT was not.

“While there have been proposals tocreate linear algorithms to modify the GATdata in eyes after laser ablation refractivesurgery, there is no scientific basis tosupport that approach because there is onlya weak positive correlation between theGAT IOP and central pachymetry.We knowGoldmann IOP generally drops after radialkeratotomy and hyperopic LASIK.Thoseprocedures induce little change in centralpachymetry but do have a profound effecton corneal rigidity.Therefore, moreaccurate measures of IOP will requireinstrumentation that performs dynamicrather than static applanationmeasurements and therefore assesses andcompensates for corneal biomechanics,” DrPepose said.

EuroTimes December 2005

“There appears to besome interlamellarhealing during the firstyear after LASIK whileover the long-term,some re-stiffeningappears to occur in eyesthat undergo PRK,”

Jesper Hjortdal MD

“These findingsunderline theimportance ofunderstanding cornealbiomechanics in orderto refine ablationpattern algorithms,”

Michael Knorz MD

“More accuratemeasures of IOP will requireinstrumentation thatperforms dynamicrather than staticapplanationmeasurements andtherefore assesses andcompensates forcorneal biomechanics,”

Jay Pepose MD PhD

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Tangential and axial difference maps (Orbscan II) after LASIK cut without ablation. Note the peripheral steepening.

Tangential and axial difference maps (Orbscan II) after laser ablation. Note the peripheral steepening.

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Adding another dimensionIoannis G. Pallikaris MD PhD, Institute ofVision and Optics, Crete, approaches thesubject of the consequences of refractivesurgery on corneal biomechanics with abroader view. Recognising that the corneais just one part of a larger organ, he isconsidering responses elsewhere in the

globe and how theymay modulatecharacteristics ofcorneal stress. DrPallikaris isinvestigatingrelationshipsbetween ocularrigidity, whichexpresses theelastic properties ofthe entire globe,blood flow, and thecornea.

He explained thatthe cornea is a livingstructure that existsunder acontinuouslyfluctuating pressureload as a result ofthe pulsatile bloodflow in the choroid.

When the corneais ablated inrefractive surgery,the stress localisedat the cornea maybe increased, despitethe fact that thesystem is continuingto work under thesame pressure.Thatchange may causethe cornea to bendoutwards, affectingits final curvature.The risk of ectasiamay be associated to

the temporal characteristics andfluctuation amplitude of the pressure loadon the cornea.

However, responses elsewhere in theglobe must also be taken into account, andin that regard, it is important to considerthe fact that highly myopic eyes may haverelatively thin scleras.Therefore, it seems

reasonable that tissue relaxationposteriorly, away from the cornea, mayresult to reduced corneal stress in thoseeyes after the cornea is ablated.

“According to this model, the localisedstress on the cornea may be relativelyreduced in highly myopic eyes with thinwalls and low rigidity. Perhaps that explainswhy ectasia is more of a problem in eyesthat have been treated for between -6 and-10 D of spherical error than it is forhigher myopes. Studies we have performedindicate ocular rigidity is not stronglyrelated to corneal biomechanics. However,ocular rigidity can modulate thecharacteristics of corneal stress. Its role inkeratectasia needs to be investigated,” DrPallikaris said.

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“According to thismodel, the localisedstress on the corneamay be relativelyreduced in highlymyopic eyes with thinwalls and low rigidity.”

Ioannis Pallikaris MD PhD

The Ocular Response Analyzer (Reichert) (left) is a non-contact device that utilizes a collimated air pulse toapplanate the cornea, along with an infrared electro-optical detection system (right).

The Pascal Dynamic Contour Tonometer (Zeimer) (left) utilises the “principle of Pascal” that when the contours ofthe cornea and tonometer match, then the pressure measured at the surface of the eye equals the pressure inside

the eye (right).

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Cynthia Roberts PhDTorrence A. Makley Research ProfessorDepartment of OphthalmologyAssociate Director, Biomedical Engineering The Ohio State Universityroberts2@vision.bme.ohio-state.edu

Kieth Meek PhDStructural Biophysics GroupSchool of Optometry and Vision Sciences, Cardiff University, UKmeekkm@cf.ac.uk

William J. Dupps MD PhDCole Eye Institute, Cleveland, Ohio, USA bjdupps@sbcglobal.net

Sunil Shah MDThe Midland Eye Institute, Birmingham, UKsunilshah@doctors.net.uk

Jay Pepose MDProfessor of Clinical Ophthalmology andVisual SciencesWashington University School of MedicineSt. Louis, Missouri, USAjpepose@peposevision.com

Jesper Hjortdal MDDepartment of OphthalmologyÅrhus University Hospital, Denmarkjesper.hjortdal@dadlnet.dk

Michael C. Knorz MD,FreeVis LASIK Center, University Medical CenterMannheim, Germanyknorz@eyes.de

Ioannis G. Pallikaris MD PhDInstitute of Vision and OpticsUniversity of Crete, Greece pallikar@med.uoc.gr