In vivo Measurement of Corneal Stiffness and Intraocular Pressure to Enable Personalised Disease Management and Treatment

In ophthalmology, accurate measurement of intraocular pressure (IOP) and in vivo measurement of corneal material stiffness have been long-standing problems. Access to this information would transform the diagnosis and therapy of diseases and conditions such as glaucoma, refractive errors and keratoconus that are currently affecting over 50% of the world population. The aim of this study is to develop new methods for the accurate measurement of IOP and corneal material stiffness in vivo. To achieve this goal, a mathematical method was developed to analyse tomography data of keratoconic corneas, to estimate the area, height and location of the keratoconic cone. This information was utilised in the development of representative numerical models of the ocular globe. A large parametric study was then conducted, and with the aid of custom-built programming tools, high-performance computing and optimisation techniques, new methods were developed. These methods enabled the use of information obtained from a non-contact tonometry device to estimate biomechanically corrected IOP and corneal material stiffness. Methods developed in this study were validated on data collected from experimental tests as well as a large clinical database obtained from four continents. The results showed that the newly developed methods for measuring IOP are more accurate than those currently available in the market. IOP measurements were stable when compared in pre and post-surgical procedures such as refractive correction or corneal crosslinking. IOP values showed a weak/no correlation with geometrical or biomechanical parameters. Further methods for measuring corneal biomechanics in-vivo showed notable advancements compared to the existing method. Biomechanical values were weakly/not correlated with IOP and geometrical features while strongly correlated with age as an indication of changes in material stiffness. The experimental validation showed excellent agreement between the in-vivo measurements in comparison to ex-vivo findings. The outcome of this research will have an impact on the better diagnosis of glaucoma by eliminating misdiagnosis due to IOP measurement inaccuracies. Further, it enables personalised disease management and treatment through in-vivo measurement of corneal biomechanics that leads to optimisation of surgical procedures, most notably corneal crosslinking and refractive surgeries

Simulation of Air Puff Tonometry Test Using Arbitrary Lagrangian-Eulerian (ALE) Deforming Mesh for Corneal Material Characterisation

Purpose: To improve numerical simulation of the non-contact tonometry test by using Arbitrary Eulerian-Lagrangian deforming mesh in the coupling between computational fluid dynamics model of an air jet and finite element model of the human eye. Methods: Computational fluid dynamics model simulated impingement of the air puff and consisted of 25920 wedge6 elements and employed Spallart-Allmaras model to simulate capture turbulence of the air jet. The time span of the jet wais 30 ms and maximum Reynolds numbe

Determination and mapping of corneal stiffness in keratoconic corneas

Purpose This research addresses an unmet clinical need by making it possible to estimate corneal biomechanical stiffness in vivo and how it varies across corneal surface in keratoconic corneas. Conclusion With this technology, clinicians can achieve a number of important goals: (1) estimate magnitude and distribution of stiffness in a KC cornea and use them to optimise the CXL treatment, (2) accurately quantify the disease progression and decide when intervention was needed, and (3) estimate magnitude and distribution of stiffness post-CXL to determine the effectiveness of the treatment. Materials and Methods While it is well known that keratoconus (KC) leads to tissue softening, the degree by which this softening takes place cannot still be determined clinically and hence cannot be used in the optimisation of collagen cross-linking (CXL) treatment. An added difficulty is the expectation that KC would not have a uniform effect on the cornea, but rather the softening would be concentrated at and around the KC cone. This research addresses these two challenges and presents technology that can estimate the magnitude and distribution of mechanical stiffness across corneal tissue. The technology is based on representative numerical modelling, leading to an algorithm for estimating the full stress-strain relationship for corneal tissue, which can then provide values of the tangent modulus at any stress or intraocular pressure level. The next step relies on the proven link between the distribution of collagen fibrils in corneal tissue and the distribution of mechanical stiffness. It uses microstructure maps of both healthy and KC corneas to translate the stiffness value obtained from the algorithm into a map of stiffness across corneal surface. Results In preliminary results, a clear difference is observed between normal and keratoconic eyes. A relative reduction of up to 70% of the total collagen fibrils is present inside the cone area. The cone position and dimensions can be evaluated with this method

Experimental evaluation of stiffening effect induced by UVA/Riboflavin corneal cross-linking using intact porcine eye globes

UVA/riboflavin corneal cross-linking (CXL) is a common used approach to treat progressive keratoconus. This study aims to investigate the alteration of corneal stiffness following CXL by mimicking the inflation of the eye under the in vivo loading conditions. Seven paired porcine eye globes were involved in the inflation test to examine the corneal behaviour. Cornea-only model was constructed using the finite element method, without considering the deformation contribution from sclera and limbus. Inverse analysis was conducted to calibrate the non-linear material behaviours in order to reproduce the inflation test. The corneal stress and strain values were then extracted from the finite element models and tangent modulus was calculated under stress level at 0.03 MPa. UVA/riboflavin cross-linked corneas displayed a significant increase in the material stiffness. At the IOP of 27.25 mmHg, the average displacements of corneal apex were 307 ± 65 μm and 437 ± 63 μm (p = 0.02) in CXL and PBS corneas, respectively. Comparisons performed on tangent modulus ratios at a stress of 0.03 MPa, the tangent modulus measured in the corneas treated with the CXL was 2.48 ± 0.69, with a 43±24% increase comparing to its PBS control. The data supported that corneal material properties can be well-described using this inflation methods following CXL. The inflation test is valuable for investigating the mechanical response of the intact human cornea within physiological IOP ranges, providing benchmarks against which the numerical developments can be translated to clinic