Impact of Tissue Damage and Hemodynamics on Restenosis Following Percutaneous Transluminal Angioplasty: A Patient-Specific Multiscale Model.

Multiscale agent-based modeling frameworks have recently emerged as promising mechanobiological models to capture the interplay between biomechanical forces, cellular behavior, and molecular pathways underlying restenosis following percutaneous transluminal angioplasty (PTA). However, their applications are mainly limited to idealized scenarios. Herein, a multiscale agent-based modeling framework for investigating restenosis following PTA in a patient-specific superficial femoral artery (SFA) is proposed. The framework replicates the 2-month arterial wall remodeling in response to the PTA-induced injury and altered hemodynamics, by combining three modules: (i) the PTA module, consisting in a finite element structural mechanics simulation of PTA, featuring anisotropic hyperelastic material models coupled with a damage formulation for fibrous soft tissue and the element deletion strategy, providing the arterial wall damage and post-intervention configuration, (ii) the hemodynamics module, quantifying the post-intervention hemodynamics through computational fluid dynamics simulations, and (iii) the tissue remodeling module, based on an agent-based model of cellular dynamics. Two scenarios were explored, considering balloon expansion diameters of 5.2 and 6.2 mm. The framework captured PTA-induced arterial tissue lacerations and the post-PTA arterial wall remodeling. This remodeling process involved rapid cellular migration to the PTA-damaged regions, exacerbated cell proliferation and extracellular matrix production, resulting in lumen area reduction up to 1-month follow-up. After this initial reduction, the growth stabilized, due to the resolution of the inflammatory state and changes in hemodynamics. The similarity of the obtained results to clinical observations in treated SFAs suggests the potential of the framework for capturing patient-specific mechanobiological events occurring after PTA intervention.

Serial RV wall stress measurements: association with right ventricular function in repaired Tetralogy of Fallot patients.

Background: Optimal timing of pulmonary valve replacement (PVR) in Tetralogy of Fallot (TOF) patients remains challenging. Ventricular wall stress is considered to be an early marker of right ventricular (RV) dysfunction. Objectives: To investigate the association of RV wall stresses and their change over time with functional parameters in TOF patients. Methods: Ten TOF patients after surgical repair with moderate/severe pulmonary regurgitation were included. At two timepoints (median follow-up time 7.2 years), patient-specific computational biventricular models for wall stress assessment were created using CMR short-axis cine images and echocardiography-based RV pressures. RV ejection fraction (RVEF), NT-proBNP and cardiopulmonary exercise tests were used as outcome measures reflecting RV function. Associations between regional RV diastolic wall stress and RV function were investigated using linear mixed models. Results: Increased wall stress correlated with lower RV mass (rrm = -0.70, p = 0.017) and lower RV mass-to-volume (rrm = -0.80, p = 0.003) using repeated measures. Wall stress decreased significantly over time, especially in patients with a stable RVEF (p < 0.001). Higher wall stress was independently associated with lower RVEF, adjusted for left ventricular ejection fraction, RV end-diastolic volume and time since initial surgery (decrease of 1.27% RVEF per kPa increase in wall stress, p = 0.029) using repeated measurements. No association was found between wall stress, NT-proBNP, and exercise capacity. Conclusions: Using a computational method to calculate wall stress locally in geometrically complex ventricles, we demonstrated that lower wall stress might be important to maintain ventricular function. RV wall stress assessment can be used in serial follow-up, and is potentially an early marker of impending RV dysfunction.

In silico thrombectomy trials for acute ischemic stroke.

BACKGROUND AND OBJECTIVE: In silico trials aim to speed up the introduction of new devices in clinical practice by testing device design and performance in different patient scenarios and improving patient stratification for optimizing clinical trials. In this paper, we demonstrate an in silico trial framework for thrombectomy treatment of acute ischemic stroke and apply this framework to compare treatment outcomes in different subpopulations and with different thrombectomy stent-retriever devices. We employ a novel surrogate thrombectomy model to evaluate the thrombectomy success in the in silico trial. METHODS: The surrogate thrombectomy model, built using data from a fine-grained finite-element model, is a device-specific binary classifier (logistic regression), to estimate the probability of successful recanalization, the outcome of interest. We incorporate this surrogate model within our previously developed in silico trial framework and demonstrate its use with three examples of in silico clinical trials. The first trial is a validation trial for the surrogate thrombectomy model. We then present two exploratory trials: one evaluating the performance of a commercially available device based on the fibrin composition in the occluding thrombus and one comparing the performance of two commercially available stent retrievers. RESULTS: The Validation Trial showed the surrogate thrombectomy model was able to reproduce a similar recanalization rate as the real-life MR CLEAN trial (p=0.6). Results from the first exploratory trial showed that the chance of successful thrombectomy increases with higher blood cell concentrations in the thrombi, which is in line with observations from clinical data. The second exploratory trial showed improved recanalization success with a newer stent retriever device; however, these results require further investigation as the surrogate model for the newer stent retriever device has not yet been validated. CONCLUSIONS: In this novel study, we have shown that in silico trials have the potential to help inform medical device developers on the performance of a new device and may also be used to select populations of interest for a clinical trial. This would reduce the time and costs involved in device development and traditional clinical trials.

A low dimensional surrogate model for a fast estimation of strain in the thrombus during a thrombectomy procedure.

BACKGROUND: Intra-arterial thrombectomy is the main treatment for acute ischemic stroke due to large vessel occlusions and can consist in mechanically removing the thrombus with a stent-retriever. A cause of failure of the procedure is the fragmentation of the thrombus and formation of micro-emboli, difficult to remove. This work proposes a methodology for the creation of a low-dimensional surrogate model of the mechanical thrombectomy procedure, trained on realizations from high-fidelity simulations, able to estimate the evolution of the maximum first principal strain in the thrombus. METHOD: A parametric finite-element model was created, composed of a tapered vessel, a thrombus, a stent-retriever and a catheter. A design of experiments was conducted to sample 100 combinations of the model parameters and the corresponding thrombectomy simulations were run and post-processed to extract the maximum first principal strain in the thrombus during the procedure. Then, a surrogate model was built with a combination of principal component analysis and Kriging. RESULTS: The surrogate model was chosen after a sensitivity analysis on the number of principal components and was tested with 10 additional cases. The model provided predictions of the strain curves with correlation above 0.9 and a maximum error of 28%, with an error below 20% in 60% of the test cases. CONCLUSIONS: The surrogate model provides nearly instantaneous estimates and constitutes a valuable tool for evaluating the risk of thrombus rupture during pre-operative planning for the treatment of acute ischemic stroke.

Multiscale agent-based modeling of restenosis after percutaneous transluminal angioplasty: Effects of tissue damage and hemodynamics on cellular activity.

BACKGROUND: Restenosis following percutaneous transluminal angioplasty (PTA) in femoral arteries is a major cause of failure of the revascularization procedure. The arterial wall response to PTA is driven by multifactorial, multiscale processes, whose complete understanding is lacking. Multiscale agent-based modeling frameworks, simulating the network of mechanobiological events at cell-tissue scale, can contribute to decipher the pathological pathways of restenosis. In this context, the present study proposes a fully-automated multiscale agent-based modeling framework simulating the arterial wall remodeling due to the wall damage provoked by PTA and to the altered hemodynamics in the post-operative months. METHODS: The framework, applied to an idealized femoral artery model, integrated: (i) a PTA module (i.e., structural mechanics simulation), computing the post-PTA arterial morphology and the PTA-induced damage (ii) a hemodynamics module (i.e., computational fluid dynamics simulations), quantifying the near-wall hemodynamics, and (iii) a tissue remodeling module simulating cellular activities through an agent-based model. RESULTS: The framework was able to capture relevant features of the 3-month arterial wall response to PTA, namely (i) the impact of the PTA-induced damage and altered hemodynamics on arterial wall remodeling, including the local intimal growth at the most susceptible regions (i.e., elevated damage levels and low wall shear stress), (ii) the lumen area temporal trend resulting from the interaction of the two inputs, and (iii) a 3-month lumen area restenosis of ∼25%, in accordance with clinical evidence. CONCLUSIONS: The overall results demonstrated the framework potentiality in capturing mechanobiological processes underlying restenosis, thus fostering future application to patient-specific scenarios.

A predictive multiscale model of in-stent restenosis in femoral arteries: linking haemodynamics and gene expression with an agent-based model of cellular dynamics.

In-stent restenosis (ISR) is a maladaptive inflammatory-driven response of femoral arteries to percutaneous transluminal angioplasty and stent deployment, leading to lumen re-narrowing as consequence of excessive cellular proliferative and synthetic activities. A thorough understanding of the underlying mechanobiological factors contributing to ISR is still lacking. Computational multiscale models integrating both continuous- and agent-based approaches have been identified as promising tools to capture key aspects of the complex network of events encompassing molecular, cellular and tissue response to the intervention. In this regard, this work presents a multiscale framework integrating the effects of local haemodynamics and monocyte gene expression data on cellular dynamics to simulate ISR mechanobiological processes in a patient-specific model of stented superficial femoral artery. The framework is based on the coupling of computational fluid dynamics simulations (haemodynamics module) with an agent-based model (ABM) of cellular activities (tissue remodelling module). Sensitivity analysis and surrogate modelling combined with genetic algorithm optimization were adopted to explore the model behaviour and calibrate the ABM parameters. The proposed framework successfully described the patient lumen area reduction from baseline to one-month follow-up, demonstrating the potential capabilities of this approach in predicting the short-term arterial response to the endovascular procedure.

Development of a patient-specific cerebral vasculature fluid-structure-interaction model.

Development of in-silico models of patient-specific cerebral artery networks presents several significant technical challenges: (i) The resolution and smoothness of medical CT images are much lower than the required element/cell length for FEA/CFD/FSI models; (ii) contact between vessels, and indeed self contact of high tortuosity vessel segments are not clearly identifiable from medical CT images. Commercial model construction software does not provide customised solutions for such technical challenges, with the result that accurate, efficient and automated development of patient-specific models of the cerebral vessels is not facilitated. This paper presents the development of a customised and highly automated platform for the generation of high resolution patient-specific FEA/CFD/FSI models from clinical images. This platform is used to perform the first fluid-structure-interaction patient-specific analysis of blood flow and artery deformation of an occluded cerebral vessel. Results demonstrate that in addition to flow disruption, clot occlusion significantly alters the geometry and strain distribution in the vessel network, with the blocked M2 segment undergoing axial elongation. The new computational approach presented in this study can be further developed as a clinical diagnostic tool and as a platform for thrombectomy device design.

Analysis of vulnerability to reentry in acute myocardial ischemia using a realistic human heart model.

Electrophysiological alterations of the myocardium caused by acute ischemia constitute a pro-arrhythmic substrate for the generation of potentially lethal arrhythmias. Experimental evidence has shown that the main components of acute ischemia that induce these electrophysiological alterations are hyperkalemia, hypoxia (or anoxia in complete artery occlusion), and acidosis. However, the influence of each ischemic component on the likelihood of reentry is not completely established. Moreover, the role of the His-Purkinje system (HPS) in the initiation and maintenance of arrhythmias is not completely understood. In the present work, we investigate how the three components of ischemia affect the vulnerable window (VW) for reentry using computational simulations. In addition, we analyze the role of the HPS on arrhythmogenesis. A 3D biventricular/torso human model that includes a realistic geometry of the central and border ischemic zones with one of the most electrophysiologically detailed model of ischemia to date, as well as a realistic cardiac conduction system, were used to assess the VW for reentry. Four scenarios of ischemic severity corresponding to different minutes after coronary artery occlusion were simulated. Our results suggest that ischemic severity plays an important role in the generation of reentries. Indeed, this is the first 3D simulation study to show that ventricular arrhythmias could be generated under moderate ischemic conditions, but not in mild and severe ischemia. Moreover, our results show that anoxia is the ischemic component with the most significant effect on the width of the VW. Thus, a change in the level of anoxia from moderate to severe leads to a greater increment in the VW (40 ms), in comparison with the increment of 20 ms and 35 ms produced by the individual change in the level of hyperkalemia and acidosis, respectively. Finally, the HPS was a necessary element for the generation of approximately 17% of reentries obtained. The retrograde conduction from the myocardium to HPS in the ischemic region, conduction blocks in discrete sections of the HPS, and the degree of ischemia affecting Purkinje cells, are suggested as mechanisms that favor the generation of ventricular arrhythmias.

Impact of the Internal Carotid Artery Morphology on in silico Stent-Retriever Thrombectomy Outcome.

The aim of this work is to propose a methodology for identifying relationships between morphological features of the cerebral vasculature and the outcome of in silico simulations of thrombectomy, the mechanical treatment for acute ischemic stroke. Fourteen patient-specific cerebral vasculature segmentations were collected and used for geometric characterization of the intracranial arteries mostly affected by large vessel occlusions, i.e., internal carotid artery (ICA), middle cerebral artery (MCA) and anterior cerebral artery (ACA). First, a set of global parameters was created, including the geometrical information commonly provided in the clinical context, namely the total length, the average diameter and the tortuosity (length over head-tail distance) of the intracranial ICA. Then, a more exhaustive geometrical analysis was performed to collect a set of local parameters. A total of 27 parameters was measured from each patient-specific vascular configuration. Fourteen virtual thrombectomy simulations were performed with a blood clot with the same length and composition placed in the middle of the MCA. The model of TREVO ProVue stent-retriever was used for all the simulations. Results from simulations produced five unsuccessful outcomes, i.e., the clot was not removed from the vessels. The geometric parameters of the successful and unsuccessful simulations were compared to find relations between the vascular geometry and the outcome. None of the global parameters alone or combined proved able to discriminate between positive and negative outcome, while a combination of local parameters allowed to correctly identify the successful from the unsuccessful simulations. Although these results are limited by the number of patients considered, this study indicates a promising methodology to relate patient-specific geometry to virtual thrombectomy outcome, which might eventually guide decision making in the treatment of acute ischemic stroke.

A response surface optimization approach to adjust ionic current conductances of cardiac electrophysiological models. Application to the study of potassium level changes.

Cardiac electrophysiological computational models are often developed from previously published models. The new models may incorporate additional features to adapt the model to a different species or may upgrade a specific ionic formulation based on newly available experimental data. A relevant challenge in the development of a new model is the estimation of certain ionic current conductances that cannot be reliably identified from experiments. A common strategy to estimate those conductances is by means of constrained non-linear least-squares optimization. In this work, a novel methodology is proposed for estimation of ionic current conductances of cardiac electrophysiological models by using a response surface approximation-based constrained optimization with trust region management. Polynomial response surfaces of a number of electrophysiological markers were built using statistical sampling methods. These markers included action potential duration (APD), triangulation, diastolic and systolic intracellular calcium concentration, and time constants of APD rate adaptation. The proposed methodology was applied to update the Carro et al. human ventricular action potential model after incorporation of intracellular potassium ([K+]i) dynamics. While the Carro et al. model was well suited for investigation of arrhythmogenesis, it did not allow simulation of [K+]i changes. With the methodology proposed in this study, the updated Carro et al. human ventricular model could be used to simulate [K+]i changes in response to varying extracellular potassium ([K+]o) levels. Additionally, it rendered values of evaluated electrophysiological markers within physiologically plausible ranges. The optimal values of ionic current conductances in the updated model were found in a notably shorter time than with previously proposed methodologies. As a conclusion, the response surface optimization-based approach proposed in this study allows estimating ionic current conductances of cardiac electrophysiological computational models while guaranteeing replication of key electrophysiological features and with an important reduction in computational cost with respect to previously published approaches. The updated Carro et al. model developed in this study is thus suitable for the investigation of arrhythmic risk-related conditions, including those involving large changes in potassium concentration.

The Effect of Cell Morphology on the Permeability of the Nuclear Envelope to Diffusive Factors.

A recent advance in understanding stem cell differentiation is that the cell is able to translate its morphology, i.e., roundish or spread, into a fate decision. We hypothesize that strain states in the nuclear envelope (NE) cause changes in the structure of the nuclear pore complexes. This induces significant changes in the NE's permeability to the traffic of the transcription factors involved in stem cell differentiation which are imported into the nucleus by passive diffusion. To demonstrate this, we set up a numerical model of the transport of diffusive molecules through the nuclear pore complex (NPC), on the basis of the NPC deformation. We then compared the prediction of the model for two different cell configurations with roundish and spread nuclear topologies with those measured on cells cultured in both configurations. To measure the geometrical features of the NPC, using electron tomography we reconstructed three-dimensional portions of the envelope of cells cultured in both configurations. We found non-significant differences in both the shape and size of the transmembrane ring of single pores with envelope deformation. In the numerical model, we thus assumed that the changes in pore complex permeability, caused by the envelope strains, are due to variations in the opening configuration of the nuclear basket, which in turn modifies the porosity of the pore complex mainly on its nuclear side. To validate the model, we cultured cells on a substrate shaped as a spatial micro-grid, called the "nichoid," which is nanoengineered by two-photon laser polymerization, and induces a roundish nuclear configuration in cells adhering to the nichoid grid, and a spread configuration in cells adhering to the flat substrate surrounding the grid. We then measured the diffusion through the nuclear envelope of an inert green-fluorescent protein, by fluorescence recovery after photobleaching (FRAP). Finally, we compared the diffusion times predicted by the numerical model for roundish vs. spread cells, with the measured times. Our data show that cell stretching modulates the characteristic time needed for the nuclear import of a small inert molecule, GFP, and the model predicts a faster import of diffusive molecules in the spread compared to roundish cells.

Factors affecting basket catheter detection of real and phantom rotors in the atria: A computational study.

Anatomically based procedures to ablate atrial fibrillation (AF) are often successful in terminating paroxysmal AF. However, the ability to terminate persistent AF remains disappointing. New mechanistic approaches use multiple-electrode basket catheter mapping to localize and target AF drivers in the form of rotors but significant concerns remain about their accuracy. We aimed to evaluate how electrode-endocardium distance, far-field sources and inter-electrode distance affect the accuracy of localizing rotors. Sustained rotor activation of the atria was simulated numerically and mapped using a virtual basket catheter with varying electrode densities placed at different positions within the atrial cavity. Unipolar electrograms were calculated on the entire endocardial surface and at each of the electrodes. Rotors were tracked on the interpolated basket phase maps and compared with the respective atrial voltage and endocardial phase maps, which served as references. Rotor detection by the basket maps varied between 35-94% of the simulation time, depending on the basket's position and the electrode-to-endocardial wall distance. However, two different types of phantom rotors appeared also on the basket maps. The first type was due to the far-field sources and the second type was due to interpolation between the electrodes; increasing electrode density decreased the incidence of the second but not the first type of phantom rotors. In the simulations study, basket catheter-based phase mapping detected rotors even when the basket was not in full contact with the endocardial wall, but always generated a number of phantom rotors in the presence of only a single real rotor, which would be the desired ablation target. Phantom rotors may mislead and contribute to failure in AF ablation procedures.

Why Non-contact Tonometry Tests Cannot Evaluate the Effects of Corneal Collagen Cross-linking.

PURPOSE: To assess the feasibility of characterizing and following up the mechanical behavior of the corneal tissue after corneal cross-linking (CXL) by using a combined mechanical (in vivo indentation and in vitro uniaxial tensile tests) and morphological (immunohisto-chemistry) experimental protocol. METHODS: CXL (3 mW/cm2; 370 nm) for 20 minutes (total dose 3.6 J/cm2) was performed on 12 New Zealand rabbits. The mechanical behavior of the cornea was characterized in small and large strain regimens using an in vivo indentation test with a laboratory device and an in vitro uniaxial tensile test, respectively. These tests and corneal immunohistochemistry were performed before (PreCXL) and on the 7th (PostCXL-7d) and 56th days (PostCXL-56d) after CXL. The intraocular pressure and corneal thickness were measured before each test. RESULTS: For the indentation tests, significant differences were found between PreCXL and PostCXL-7d and between PostCXL-7d and PostCXL-56d, but not between PreCXL and PostCXL-56d. On average, for the small strain regimen, PostCXL-7d corneas showed the most compliant behavior, with progressive recovery of the corneal stiffness over time. For the large strain regimen, significant differences in the maximum tangent modulus between PreCXL and PostCXL-7d and between PreCXL and PostCXL-56d were observed for the uniaxial tensile tests, with no significant differences between PostCXL-7d and PostCXL-56d. Immunohistochemistry showed a lack of cells in the anterior stroma at PostCXL-7d, but at PostCXL-56d the cell density and morphology were comparable to PreCXL. CONCLUSIONS: Indentation tests cannot characterize the changes in the corneal collagen scaffold caused by the CXL, but the uniaxial test can. However, indentation tests can assess the recovery of keratocyte density after CXL. [J Refract Surg. 2017;33(3):184-192.].

Limitations in electrophysiological model development and validation caused by differences between simulations and experimental protocols.

Models of ion channel dynamics are usually built by fitting isolated cell experimental values of individual parameters while neglecting the interaction between them. Another shortcoming regards the estimation of ionic current conductances, which is often based on quantification of Action Potential (AP)-derived markers. Although this procedure reduces the uncertainty in the calculation of conductances, many studies evaluate electrophysiological AP-derived markers from single cell simulations, whereas experimental measurements are obtained from tissue preparations. In this work, we explore the limitations of these approaches to estimate ion channel dynamics and maximum current conductances and how they could be overcome by using multiscale simulations of experimental protocols. Four human ventricular cell models, namely ten Tusscher and Panfilov (2006), Grandi et al. (2010), O'Hara et al. (2011), and Carro et al. (2011), were used. Two problems involving scales from ion channels to tissue were investigated: 1) characterization of L-type calcium voltage-dependent inactivation ICa,L; 2) identification of major ionic conductance contributors to steady-state AP markers, including APD90, APD75, APD50, APD25, Triangulation and maximal and minimal values of V and dV/dt during the AP (Vmax, Vmin, dV/dtmax, dV/dtmin). Our results show that: 1) ICa,L inactivation characteristics differed significantly when calculated from model equations and from simulations reproducing the experimental protocols. 2) Large differences were found in the ionic currents contributors to APD25, Triangulation, Vmax, dV/dtmax and dV/dtmin between single cells and 1D-tissue. When proposing any new model formulation, or evaluating an existing model, consistency between simulated and experimental data should be verified considering all involved effects and scales.

Modeling of the mechano-chemical behaviour of the nuclear pore complex: current research and perspectives.

Recent evidence suggests that mechanical deformation of the cell nucleus regulates the nuclear import of the transcriptional activators of genes involved in primary physiological cell responses such as stem cell differentiation. In addition, this nuclear mechanosensing response is de-regulated in pathological states, such as cancer and neurodegeneration. One hypothesis that could greatly advance the field is that the deformation of the nuclear envelope activates nuclear pore complexes through a direct mechanical link. The understanding of this possible mechanism for nuclear pore complex stretch-activation entails studying the mechanical connection of this complex to the nuclear envelope at the nanoscale. The nanomechanics of the nuclear pore complex is thus emerging as a novel research field, bridging nanoscience with nanotechnology. This review examines the frontier of research methodologies that are potentially useful for building a computational model of this interaction. This includes, for example, electron tomography to assess the geometrical features of the nuclear pore complex and nanoindentation to estimate its mechanical properties and that of the nuclear envelope. In order to summarize the state-of-the-art and perspectives in the field of NPC nanomechanics, this review covers highly interdisciplinary experimental and theoretical research methodologies pertaining to the fields of physics, chemistry, biology, materials and mechanics.

Patient specific stress and rupture analysis of ascending thoracic aneurysms.

An ascending thoracic aortic aneurysm (ATAA) is a serious medical condition which, more often than not, requires surgery. Aneurysm diameter is the primary clinical criterion for determining when surgical intervention is necessary but, biomechanical studies have suggested that the diameter criterion is insufficient. This manuscript presents a method for obtaining the patient specific wall stress distribution of the ATAA and the retrospective rupture risk for each patient. Five human ATAAs and the preoperative dynamic CT scans were obtained during elective surgeries to replace each patient's aneurysm with a synthetic graft. The material properties and rupture stress for each tissue sample were identified using bulge inflation tests. The dynamic CT scans were used to generate patient specific geometries for a finite element (FE) model of each patient's aneurysm. The material properties from the bulge inflation tests were implemented in the FE model and the wall stress distribution at four different pressures was estimated. Three different rupture risk assessments were compared: the maximum diameter, the rupture risk index, and the overpressure index. The peak wall stress values for the patients ranged from 28% to 94% of the ATAA's failure stress. The rupture risk and overpressure indices were both only weakly correlated with diameter (ρ=-0.29, both cases). In the future, we plan to conduct a large experimental and computational study that includes asymptomatic patients under surveillance, patients undergoing elective surgery, and patients who have experienced rupture or dissection to determine if the rupture risk index or maximum diameter can meaningfully differentiate between the groups.

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.