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

Investigation of the corneal frequency response to modulated sound excitation

Purpose : To investigate the possibility of determining the eye's intraocular pressure (IOP), biomechanical parameters (BM), and geometrical distortion through its frequency response to acoustic excitation as measured by phase-sensitive swept source optical coherence tomography (PhS-ssOCT). Methods : Experimental (E): Freshly enucleated porcine eyes (<45h) were mounted in front of a PhS-ssOCT at 15mmHg IOP. A loudspeaker was placed 10mm to the corneal apex, and a frequency sweep (0-1000Hz) was applied at sound pressure levels of 0.88Pa. Resonance amplitude and frequency were measured for different corneal treatments: 1) de-epithelized, 2) applied photosensitizer Riboflavin (RF), 3) cross-linked (CXL, Dresden protocol), and different measurement set-ups: a) at/around apex, b) IOP 15 - 30 mmHg, c) eye mounted on artificial orbital fat, mimicked by silicone. Simulations (S): Nonlinear hyperelastic FE models of porcine eyes were built and subjected to a modulated pressure, equal to (E). The frequency response was determined by monitoring the apex displacement over time then using fast Fourier transformation (FFT) analysis to determine the frequency peaks. Resonance frequency and amplitudes were determined across corneal meridians for homogeneous BM and for corneas with local BM variations. For both (E) and (S), resonance frequencies were defined at the positions of peak amplitudes. Results : (S) and (E) results were in good correspondence and both showed resonance frequencies of 370Hz. An increase of 15 mmHg in IOP resulted in a decrease of the resonance amplitude of up to 1.24±0.61μm (E) and a frequency shift of up to 22.7± 9.3Hz (E). BM changes produced by CXL led to a decrease in amplitude of 2.19±0.78μm, without significant frequency shifts (E). (S) supported these trends, but showed up to 13Hz higher frequency shifts with IOP increase. Additionally, (S) showed that localized BM changes could be detected by examining asymmetries of the resonance amplitude across opposite corneal meridians. Presence of artificial orbital fat resulted in a damping of the resonance amplitude of >50% for (E) and (S). Conclusions : Sound-coupled OCT measurements made it possible to detect corneal resonance frequencies. IOP and BM could be decoupled, due to differential dependencies of amplitude and resonance frequency on IOP and BM