Coupled Biomechanical Response of the Cornea Assessed by Non-Contact Tonometry. A Simulation Study

The mechanical response of the cornea subjected to a non-contact air-jet tonometry diagnostic test represents an interplay between its geometry, the corneal material behavior and the loading. The objective is to study this interplay to better understand and interpret the results obtained with a non-contact tonometry test. A patient-specific finite element model of a healthy eye, accounting for the load free configuration, was used. The corneal tissue was modeled as an anisotropic hyperelastic material with two preferential directions. Three different sets of parameters within the human experimental range obtained from inflation tests were considered. The influence of the IOP was studied by considering four pressure levels (10–28 mmHg) whereas the influence of corneal thickness was studied by inducing a uniform variation (300–600 microns). A Computer Fluid Dynamics (CFD) air-jet simulation determined pressure loading exerted on the anterior corneal surface. The maximum apex displacement showed a linear variation with IOP for all materials examined. On the contrary, the maximum apex displacement followed a cubic relation with corneal thickness. In addition, a significant sensitivity of the apical displacement to the corneal stiffness was also obtained. Explanation to this behavior was found in the fact that the cornea experiences bending when subjected to an air-puff loading, causing the anterior surface to work in compression whereas the posterior surface works in tension. Hence, collagen fibers located at the anterior surface do not contribute to load bearing. Non-contact tonometry devices give useful information that could be misleading since the corneal deformation is the result of the interaction between the mechanical properties, IOP, and geometry. Therefore, a non-contact tonometry test is not sufficient to evaluate their individual contribution and a complete in-vivo characterization would require more than one test to independently determine the membrane and bending corneal behavior.The research leading these results has received funding from the European Union’s Seven Framework Program managed by REA Research Executive agency http://ec.europa.eu/research/rea (FP7/2007-2013) under Grant Agreement n° FP7-SME-2013 606634 and the Spanish Ministry of Economy and Competitiveness (DPI2011-27939-C02-01)

A predictive tool for determining patient-specific mechanical properties of human corneal tissue

A computational predictive tool for assessing patient-specific corneal tissue properties is developed. This predictive tool considers as input variables the corneal central thickness (CCT), the intraocular pressure (IOP), and the maximum deformation amplitude of the corneal apex (U) when subjected to a non-contact tonometry test. The proposed methodology consists of two main steps. First, an extensive dataset is generated using Monte Carlo (MC) simulations based on finite element models with patient-specific geometric features that simulate the non-contact tonometry test. The cornea is assumed to be an anisotropic tissue to reproduce the experimentally observed mechanical behavior. A clinical database of 130 patients (53 healthy, 63 keratoconic and 14 post-LASIK surgery) is used to generate a dataset of more than 9000 cases by permuting the material properties. The second step consists of constructing predictive models for the material parameters of the constitutive model as a function of the input variables. Four different approximations are explored: quadratic response surface (QRS) approximation, multiple layer perceptron (MLP), support vector regressor (SVR), and K-nn search. The models are validated against data from five real patients. The material properties obtained with the predicted models lead to a simulated corneal displacement that is within 10% error of the measured value in the worst case scenario of a patient with very advanced keratoconus disease. These results demonstrate the potential and soundness of the proposed methodology.The research leading to these results has received funding from the European Union’s Seven Framework Program managed by REA Research Executive agency http://ec.europa.eu/research/rea (FP7/2007–2013) under Grant Agreement FP7-SME-2013 606634, the Spanish Ministry of Economy and Competitiveness under the Grant Agreement DPI2014-54981R, the Government of Aragón (predoctoral contract of the author), the Ibercaja-CAI mobility program (mobility funding for research stay of the author) and the Swiss Federal Department of Economic Affairs, Education and Research (Federal Commission for Scholarships for Foreign Students)

Augmented acquisition of cocaine self-administration and altered brain glucose metabolism in adult female but not male rats exposed to a cannabinoid agonist during adolescence

Marijuana consumption during adolescence has been proposed to be a stepping stone for adult cocaine addiction. However, experimental evidence for this hypothesis is missing. In this work we chronically injected male and female Wistar rats with either the cannabinoid agonist CP 55,940 (CP; 0.4 mg/kg) or its corresponding vehicle. Adult acquisition (seven 30 min daily sessions) and maintenance (fourteen 2 h daily sessions) of cocaine self administration (1 mg/kg), food reinforced operant learning under conditions of normal (ad libitum access to food), and high motivation (food restriction schedule) were measured. Additionally, brain metabolic activity was analyzed by means of [18F] fluorodeoxyglucose positron emission tomography. During the acquisition phase, female CP treated rats showed a higher rate of cocaine self administration as compared to vehicle treated females and males; no differences were found between both male groups. This effect disappeared in the maintenance phase. Moreover, no differences among groups were evident in the food reinforced operant task, pointing to the cocaine specific nature of the effect seen in self administration rather than a general change in reward processing. Basal brain metabolic activity also changed in CP treated females when compared to their vehicle treated counterparts with no differences being found in the males; more specifically we observed a hyper activation of the frontal cortex and a hypo activation of the amygdalo entorhinal cortex. Our results suggest that a chronic exposure to cannabinoids during adolescence alters the susceptibility to acquire cocaine self administration, in a sex specific fashion. This increased susceptibility could be related to thechanges in brain metabolic activity induced by cannabinoids during adolescenceThis work was supported by Grants FIS G03/05 (Red de Trastornos Adictivos), BSO2001-1099, FIS 01-05-01, Plan Nacional sobre Drogas (PNSD) 2001–2003, PNSD 2004–2007, GR-SAL/0260/2004 to EA and Grants INT/2012/ 2002, CB06/01/0079, and CENIT (2006–2009) to MDPublicad

Automatized Patient-Specific Methodology for Numerical Determination of Biomechanical Corneal Response

This work presents a novel methodology for building a three-dimensional patient-specific eyeball model suitable for performing a fully automatic finite element (FE) analysis of the corneal biomechanics. The reconstruction algorithm fits and smooths the patient’s corneal surfaces obtained in clinic with corneal topographers and creates an FE mesh for the simulation. The patient’s corneal elevation and pachymetry data is kept where available, to account for all corneal geometric features (central corneal thickness–CCT and curvature). Subsequently, an iterative free-stress algorithm including a fiber’s pull-back is applied to incorporate the pre-stress field to the model. A convergence analysis of the mesh and a sensitivity analysis of the parameters involved in the numerical response is also addressed to determine the most influential features of the FE model. As a final step, the methodology is applied on the simulation of a general non-commercial non-contact tonometry diagnostic test over a large set of 130 patients—53 healthy, 63 keratoconic (KTC) and 14 post-LASIK surgery eyes. Results show the influence of the CCT, intraocular pressure (IOP) and fibers (87%) on the numerical corneal displacement (UNum), the good agreement of the UNum with clinical results, and the importance of considering the corneal pre-stress in the FE analysis. The potential and flexibility of the methodology can help improve understanding of the eye biomechanics, to help to plan surgeries, or to interpret the results of new diagnosis tools (i.e., non-contact tonometers).The research leading to these results has received funding from the European Union’s Seven Framework Program managed by REA Research Executive agency http://ec.europa.eu/research/rea (FP7/2007–2013) under Grant Agreement FP7-SME-2013 606634 and the Spanish Ministry of Economy and Competitiveness (DPI2011-27939-C02201 and DPI2014-54981R)

Fluid–structure simulation of a general non-contact tonometry. A required complexity?

Understanding corneal biomechanics is important for applications regarding refractive surgery prediction outcomes and the study of pathologies affecting the cornea itself. In this regard, non-contact tonometry (NCT) is gaining interest as a non-invasive diagnostic tool in ophthalmology, and is becoming an alternative method to characterize corneal biomechanics in vivo. In general, identification of material parameters of the cornea from a NCT test relies on the inverse finite element method, for which an accurate and reliable modelization of the test is required. This study explores four different modeling strategies ranging from pure structural analysis up to a fluid–structure interaction model considering the air–cornea and humor–cornea interactions. The four approaches have been compared using clinical biomarkers commonly used in ophthalmology. Results from the simulations indicate the importance of considering the humors as fluids and the deformation of the cornea when determining the pressure applied by the air-jet during the test. Ignoring this two elements in the modeling lead to an overestimation of corneal displacement and therefore an overestimation of corneal stiffness when using the inverse finite element method

Interaction between diurnal variations of intraocular pressure, pachymetry, and corneal response to an air puff: Preliminary evidence

Diurnal changes in corneal geometry, pachymetry, and intraocular pressure (IOP) in a healthy eye were recorded. The deformation response to an air puff was simulated using 3 levels of corneal stiffness. The response was dependent on IOP and pachymetry and not only on the biomechanical properties of the cornea. Similarly, the maximum variability due to the diurnal changes in pachymetry and IOP in the corneal displacement generated by the air puff was found to reach 5%. Therefore, diurnal changes in IOP and corneal thickness were able to induce some variability in the air puff–based corneal deformation response. This potential variability should be considered when the biomechanical properties of the cornea are analyzed with air-puff devices.Supported by the European Union’s Seventh Framework Program managed by Research Executive Agency under Grant Agreement number FP7-SME-2013 606634 (POPCORN Project) and the Spanish Ministry of Economy and Competitiveness (DPI2011-27939-C02-01)

Why Does Extracellular Potassium Rise in Acute Ischemia? Insights from Computational Smilations

[EN] Hyperkalemia, acidosis and hypoxia are the three main components of acute myocardial ischemia. In particular, the increase of extracellular K+ concentration (hyperkalemia), has been proved to be very proarrhythmic because it sets the stage for ventricular fibrillation. However, the intimate mechanisms remain partially unknown. The aim of this work was to investigate, using computational simulation, the relationship between the different phases of hiperkalemia, the activity of the ion channels and the changes related to the action potential in the absence of coronary flow. Our results show that the partial inhibition of the sodium-potassium pump is the main cause of extracellular potassium accumulation. However, the cause of the plateau phase could be due to the appearance of action potential alternans, which reduces the net potassium efflux and limits the increase of extracellular potassium concentration.This work was partially supported by the "Programa Salvador de Madariaga 2018" of the Spanish Ministry of Science, Innovation and Universities (Grant Reference PRX18/00489).González-Ascaso, A.; Olcina, P.; Garcia-Daras, M.; Rodriguez Matas, JF.; Ferrero De Loma-Osorio, JM. (2019). Why Does Extracellular Potassium Rise in Acute Ischemia? Insights from Computational Smilations. IEEE. 1-4. https://doi.org/10.22489/CinC.2019.088S1

Displacement of the corneal apex (mm) as a function of the corneal thickness (CCT).

<p>Patient’s pachymetry was constantly decreased for the simulations. Results show a cubic relation between displacement and pachymetry (CCT) when the material was fixed (large stifnees material—C) and three levels of IOP were considered: 10 mmHg (dotted-dashed green line), 19 mHg (solid green line), and 28 mmHg (doted green line). Results also show a cubic relation between displacement and pachymetry (CCT) when the IOP was kept at 19 mmHg and the three corneal stiffnesses were considered: low (material A) solid red line, intermediate (material B) solid blue line, and large (material C) solid green line. The right panel shows the accuracy of the fit (minimum mean squares) and the constants of the cubic polynomial.</p

Material parameters for cornea, limbus, and sclera.

<p>Material parameters for cornea, limbus, and sclera.</p

Displacement—Time response of the corneal apex.

<p>Time course of the apex displacement for the conducted simulations. Displacement’s region 10–28 mmHg (mat. A) (red colored area) are the results for low stiffness material (A) for all three different IOP (10, 19 and 28 mmHg); Displacement’s region 10–28 mmHg (mat. B) (blue colored area) are the results for intermediate stiffness material (B) for all three different IOP (10, 19 and 28 mmHg); Displacement’s region 10–28 mmHg (mat. C) (green colored area) are the results for large stiffness material (C) for all three different IOP (10, 19 and 28 mmHg). Different overlapping zones, at different loading time, can be observed in figure. Inverted triangles correspond to simulations performed with the real IOP (12 mmHg) and the three different corneal material models.</p