A review of corneal biomechanics: Mechanisms for measurement and the implications for refractive surgery

Detailed clinical assessment of corneal biomechanics has the potential to revolutionize the ophthalmic industry through enabling quicker and more proficient diagnosis of corneal disease, safer and more effective surgical treatments, and the provision of customized and optimized care. Despite these wide-ranging benefits, and an outstanding clinical need, the provision of technology capable of the assessment of corneal biomechanics in the clinic is still in its infancy. While laboratory-based technologies have progressed significantly over the past decade, there remain significant gaps in our knowledge regarding corneal biomechanics and how they relate to shape and function, and how they change in disease and after surgical intervention. Here, we discuss the importance, relevance, and challenges associated with the assessment of corneal biomechanics and review the techniques currently available and underdevelopment in both the laboratory and the clinic

Torsional wave elastography to assess the mechanical properties of the cornea

Corneal mechanical changes are believed to occur before any visible structural alterations observed during routine clinical evaluation. This study proposed developing an elastography technique based on torsional waves (TWE) adapted to the specificities of the cornea. By measuring the displacements in the propagation plane perpendicular to the axis of the emitter, the effect of guided waves in platelike media was proven negligible. Ex vivo experiments were carried out on porcine corneal samples considering a group of control and one group of alkali burn treatment ( NH 4OH) that modified the mechanical properties. Phase speed was recovered as a function of intraocular pressure (IOP), and a Kelvin-Voigt rheological model was fitted to the dispersion curves to estimate viscoelastic parameters. A comparison with uniaxial tensile testing with thin-walled assumptions was also performed. Both shear elasticity and viscosity correlated positively with IOP, being the elasticity lower and the viscosity higher for the treated group. The viscoelastic parameters ranged from 21.33 to 63.17 kPa, and from 2.82 to 5.30 Pa s, for shear elasticity and viscosity, respectively. As far as the authors know, no other investigations have studied this mechanical plane under low strain ratios, typical of dynamic elastography in corneal tissue. TWE reflected mechanical properties changes after treatment, showing a high potential for clinical diagnosis due to its rapid performance time and paving the way for future in vivo studies.Ministerio de Educacion, Cultura y Deporte Grant DPI2017-83859-R DPI2014-51870-R UNGR15-CE-3664 EQC2018-004508-PSpanish Government DTS15/00093 PI16/00339Instituto de Salud Carlos III y Fondos FederJunta de Andalucia PI-0107-2017 PIN-0030-2017 IE2017-5537MCIN/AEI - European Social Fund "Investing in your future" PRE2018-086085Consejeria de economia, conocimiento, empresas y universidad SOMM17/6109/UGR B-TEP-026- IE2017-5537 P18-RT-1653European Commission SOMM17/6109/UGR B-TEP-026- IE2017-5537 P18-RT-165

Multiple Optical Elastography Techniques Reveal the Regulation of Corneal Stiffness by Collagen XII

9 pags., 5 figs., 1 tab.PURPOSE. Collagen XII plays a role in regulating the structure and mechanical properties of the cornea. In this work, several optical elastography techniques were used to investigate the effect of collagen XII deficiency on the stiffness of the murine cornea. METHODS. A three-prong optical elastography approach was used to investigate the mechanical properties of the cornea. Brillouin microscopy, air-coupled ultrasonic optical coherence elastography (OCE) and heartbeat OCE were used to assess the mechanical properties of wild type (WT) and collagen XII¿deficient (Col12a1¿/¿) murine corneas. The Brillouin frequency shift, elastic wave speed, and compressive strain were all measured as a function of intraocular pressure (IOP). RESULTS. All three optical elastography modalities measured a significantly decreased stiffness in the Col12a1¿/¿ compared to the WT (P < 0.01 for all three modalities). The optical coherence elastography techniques showed that mean stiffness increased as a function of IOP; however, Brillouin microscopy showed no discernable trend in Brillouin frequency shift as a function of IOP. CONCLUSIONS. Our approach suggests that the absence of collagen XII significantly softens the cornea. Although both optical coherence elastography techniques showed an expected increase in corneal stiffness as a function of IOP, Brillouin microscopy did not show such a relationship, suggesting that the Brillouin longitudinal modulus may not be affected by changes in IOP. Future work will focus on multimodal biomechanical models, evaluating the effects of other collagen types on corneal stiffness, and in vivo measurements.Supported by the National Institutes of Health, grant numbers R01EY022362, R01EY030063, R01EY029395, R01EY028666, and P30EY007551

Interferometric Ex Vivo Evaluation of the Spatial Changes to Corneal Biomechanics Introduced by Topographic CXL: A Pilot Study

PURPOSE: To determine the efficacy of interferometry for examining the spatial changes to the corneal biomechanical response to simulated intraocular pressure (IOP) fluctuations that occur after corneal cross-linking (CXL) applied in different topographic locations. METHODS: Displacement speckle pattern interferometry (DSPI) was used to measure the total anterior surface displacement of human and porcine corneas in response to pressure variations up to 1 mm Hg from a baseline pressure of 16.5 mm Hg, both before and after CXL treatment, which was applied in isolated topographic locations (10-minute riboflavin soak [VibeX-Xtra; Avedro, Inc], 8-minute ultraviolet-A exposure at 15 mW/cm2). Alterations to biomechanics were evaluated by directly comparing the responses before and after treatment for each cornea. RESULTS: Before CXL, the corneal response to loading indicated spatial variability in mechanical properties. CXL treatments had a variable effect on the corneal response to loading dependent on the location of treatment, with reductions in regional displacement of up to 80% in response to a given pressure increase. CONCLUSIONS: Selectively cross-linking in different topographic locations introduces position-specific changes to mechanical properties that could potentially be used to alter the refractive power of the cornea. Changes to the biomechanics of the cornea after CXL are complex and appear to vary significantly depending on treatment location and initial biomechanics. Hence, further investigations are required on a larger number of corneas to allow the development of customized treatment protocols. In this study, laser interferometry was demonstrated to be an effective and valuable tool to achieve this

Noncontact elastic wave imaging optical coherence elastography for evaluating changes in corneal elasticity due to crosslinking

The mechanical properties of tissues can provide valuable information about tissue integrity and health and can assist in detecting and monitoring the progression of diseases such as keratoconus. Optical coherence elastography (OCE) is a rapidly emerging technique, which can assess localized mechanical contrast in tissues with micrometer spatial resolution. In this work we present a noncontact method of optical coherence elastography to evaluate the changes in the mechanical properties of the cornea after UV-induced collagen cross-linking. A focused air-pulse induced a low amplitude (μm scale) elastic wave, which then propagated radially and was imaged in three dimensions by a phase-stabilized swept source optical coherence tomography (PhSSSOCT) system. The elastic wave velocity was translated to Young’s modulus in agar phantoms of various concentrations. Additionally, the speed of the elastic wave significantly changed in porcine cornea before and after UV-induced corneal collagen cross-linking (CXL). Moreover, different layers of the cornea, such as the anterior stroma, posterior stroma, and inner region, could be discerned from the phase velocities of the elastic wave. Therefore, because of noncontact excitation and imaging, this method may be useful for in vivo detection of ocular diseases such as keratoconus and evaluation of therapeutic interventions such as CXL

Ocular rigidity : a previously unexplored risk factor in the pathophysiology of open-angle glaucoma : assessment using a novel OCT-based measurement method

Le glaucome est la première cause de cécité irréversible dans le monde. Bien que sa pathogenèse demeure encore nébuleuse, les propriétés biomécaniques de l’oeil sembleraient jouer un rôle important dans le développement et la progression de cette maladie. Il est stipulé que la rigidité oculaire (RO) est altérée au travers les divers stades de la maladie et qu’elle serait le facteur le plus influent sur la réponse du nerf optique aux variations de la pression intraoculaire (PIO) au sein du glaucome. Pour permettre l’investigation du rôle de la RO dans le glaucome primaire à angle ouvert (GPAO), la capacité de quantifier la RO in vivo par l’entremise d’une méthode fiable et non-invasive est essentielle. Une telle méthode n’est disponible que depuis 2015. Basée sur l'équation de Friedenwald, cette approche combine l'imagerie par tomographie par cohérence optique (TCO) et la segmentation choroïdienne automatisée afin de mesurer le changement de volume choroïdien pulsatile (ΔV), ainsi que la tonométrie dynamique de contour Pascal pour mesurer le changement de pression pulsatile correspondant. L’objectif de cette thèse est d’évaluer la validité de cette méthode, et d’en faire usage afin d’investiguer le rôle de la RO dans les maladies oculaires, particulièrement le GPAO. Plus spécifiquement, cette thèse vise à : 1) améliorer la méthode proposée et évaluer sa validité ainsi que sa répétabilité, 2) investiguer l’association entre la RO et le dommage neuro-rétinien chez les patients glaucomateux, et ceux atteints d’un syndrome de vasospasticité, 3) évaluer l’association entre la RO et les paramètres biomécaniques de la cornée, 4) évaluer l’association entre la RO et les pics de PIO survenant suite aux thérapies par injections intravitréennes (IIV), afin de les prédire et de les prévenir chez les patients à haut risque, et 5) confirmer que la RO est réduite dans les yeux myopes. D’abord, nous avons amélioré le modèle mathématique de l’oeil utilisé pour dériver ΔV en le rendant plus précis anatomiquement et en tenant compte de la choroïde périphérique. Nous avons démontré la validité et la bonne répétabilité de cette méthodologie. Puis, nous avons effectué la mesure des coefficients de RO sur un large éventail de sujets sains et glaucomateux en utilisant notre méthode non-invasive, et avons démontré, pour la première fois, qu'une RO basse est corrélée aux dommages glaucomateux. Les corrélations observées étaient comparables à celles obtenues avec des facteurs de risque reconnus tels que la PIO maximale. Une forte corrélation entre la RO et les dommages neuro-rétiniens a été observée chez les patients vasospastiques, mais pas chez ceux atteints d'une maladie vasculaire ischémique. Cela pourrait potentiellement indiquer une plus grande susceptibilité au glaucome due à la biomécanique oculaire chez les patients vasospastiques. Bien que les paramètres biomécaniques cornéens aient été largement adoptés dans la pratique clinique en tant que substitut pour la RO, propriété biomécanique globale de l'oeil, nous avons démontré une association limitée entre la RO et ces paramètres, offrant une nouvelle perspective sur la relation entre les propriétés biomécaniques cornéennes et globales de l’oeil. Seule une faible corrélation entre le facteur de résistance cornéenne et la RO demeure après ajustement pour les facteurs de confusion dans le groupe des patients glaucomateux. Ensuite, nous avons présenté un modèle pour prédire l'amplitude des pics de PIO après IIV à partir de la mesure non-invasive de la RO. Ceci est particulièrement utile pour les patients à haut risque atteints de maladies rétiniennes exsudatives et de glaucome qui nécessiteraient des IIV thérapeutiques, et pourrait permettre aux cliniciens d'ajuster ou de personnaliser le traitement pour éviter toute perte de vision additionnelle. Enfin, nous avons étudié les différences de RO entre les yeux myopes et les non-myopes en utilisant cette technique, et avons démontré une RO inférieure dans la myopie axiale, facteur de risque du GPAO. Dans l'ensemble, ces résultats contribuent à l’avancement des connaissances sur la physiopathologie du GPAO. Le développement de notre méthode permettra non seulement de mieux explorer le rôle de la RO dans les maladies oculaires, mais contribuera également à élucider les mécanismes et développer de nouveaux traitements ciblant la RO pour contrer la déficience visuelle liée à ces maladies.Glaucoma is the leading cause of irreversible blindness worldwide. While its pathogenesis is yet to be fully understood, the biomechanical properties of the eye are thought to be involved in the development and progression of this disease. Ocular rigidity (OR) is thought to be altered through disease processes and has been suggested to be the most influential factor on the optic nerve head’s response to variations in intraocular pressure (IOP) in glaucoma. To further investigate the role of OR in open-angle glaucoma (OAG) and other ocular diseases such as myopia, the ability to quantify OR in living human eyes using a reliable and non-invasive method is essential. Such a method has only become available in 2015. Based on the Friedenwald equation, the method uses time-lapse optical coherence tomography (OCT) imaging and automated choroidal segmentation to measure the pulsatile choroidal volume change (ΔV), and Pascal dynamic contour tonometry to measure the corresponding pulsatile pressure change. The purpose of this thesis work was to assess the validity of the methodology, then use it to investigate the role of OR in ocular diseases, particularly in OAG. More specifically, the objectives were: 1) To improve the extrapolation of ΔV and evaluate the method’s validity and repeatability, 2) To investigate the association between OR and neuro-retinal damage in glaucomatous patients, as well as those with concomitant vasospasticity, 3) To evaluate the association between OR and corneal biomechanical parameters, 4) To assess the association between OR and IOP spikes following therapeutic intravitreal injections (IVIs), to predict and prevent them in high-risk patients, and 5) To confirm that OR is lower in myopia. First, we improved the mathematical model of the eye used to derive ΔV by rendering it more anatomically accurate and accounting for the peripheral choroid. We also confirmed the validity and good repeatability of the method. We carried out the measurement of OR coefficients on a wide range of healthy and glaucomatous subjects using this non-invasive method, and were able to show, for the first time, that lower OR is correlated with more glaucomatous damage. The correlations observed were comparable to those obtained with recognized risk factors such as maximum IOP. A strong correlation between OR and neuro-retinal damage was found in patients with concurrent vasospastic syndrome, but not in those with ischemic vascular disease. This could perhaps indicate a greater susceptibility to glaucoma due to ocular biomechanics in vasospastic patients. While corneal biomechanical parameters have been widely adopted in clinical practice as surrogate measurements for the eye’s overall biomechanical properties represented by OR, we have shown a limited association between these parameters, bringing new insight unto the relationship between corneal and global biomechanical properties. Only a weak correlation between the corneal resistance factor and OR remained in glaucomatous eyes after adjusting for confounding factors. In addition, we presented a model to predict the magnitude of IOP spikes following IVIs from the non-invasive measurement of OR. This is particularly useful for high-risk patients with exudative retinal diseases and glaucoma that require therapeutic IVIs, and could provide the clinician an opportunity to adjust or customize treatment to prevent further vision loss. Finally, we investigated OR differences between non-myopic and myopic eyes using this technique, and demonstrated lower OR in axial myopia, a risk factor for OAG. Overall, these findings provide new insights unto the pathophysiology of glaucomatous optic neuropathy. The development of our method will permit further investigation of the role of OR in ocular diseases, contributing to elucidate mechanisms and provide novel management options to counter vision impairment caused by these diseases

Assessing the effects of riboflavin/UV-A crosslinking on porcine corneal mechanical anisotropy with optical coherence elastography

In this work we utilize optical coherence elastography (OCE) to assess the effects of UV-A/riboflavin corneal collagen crosslinking (CXL) on the mechanical anisotropy of in situ porcine corneas at various intraocular pressures (IOP). There was a distinct meridian of increased Young’s modulus in all samples, and the mechanical anisotropy increased as a function of IOP and also after CXL. The presented noncontact OCE technique was able to quantify the Young’s modulus and elastic anisotropy of the cornea and their changes as a function of IOP and CXL, opening new avenues of research for evaluating the effects of CXL on corneal biomechanical properties

Advances in Biomechanical Parameters for Screening of Refractive Surgery Candidates: A Review of the Literature, Part III

Corneal biomechanical properties have garnered significant interest in their relation to the development of ectatic corneal disease. Alongside the advent of corneal tomography and Scheimpflug imaging such as Pentacam and Galilei, there have been advances in assessing the cornea based on its biomechanical characteristics. Though the aforementioned imaging systems are highly capable of identifying morphologic abnormalities, they cannot assess mechanical stability of the cornea. This article, in contrast to Parts I and II of this article series, will focus on in vivo corneal biomechanical imaging systems. The two most readily available commercial systems include the Corvis ST and the Ocular Response Analyzer. Both of these systems aimed to characterize corneal biomechanics via distinct measurements. While in Parts I and II of this article series the authors focused on elevation, pachymetric, and keratometric data, the purpose of this article was to summarize biomechanical parameters and their clinical use in screening refractive surgery candidates. Moreover, this article explores biomechanical decompensation and its role in the development of corneal ectasia and keratoconus. There is a focus on the diagnostic accuracy of biomechanical indices in the identification of diseases such as keratoconus that may preclude a patient from undergoing refractive surgery