(451e) Non-Dimensional Analysis of Retinal Microaneurysms: Critical Threshold for Treatment

Introduction: Diabetic retinopathy is responsible for 5% of the cases of blindness worldwide and for up to 17% of the cases in the western world. Retinal microanuerysms reduce vision quality due to local loss of endothelial barrier function, causing leakage and retinal edema. Localized leakage from microaneurysms can be detected and blocked using laser ablation, slowing the progression of diabetic blindness. Our approach has been to gain a critical understanding of the fluid dynamics of the problem, which will enable us to predict risk associated with the diseased morphology. However, analytical solutions of Navier-Stokes equations governing fluid dynamics exist solely for restricted conditions, while numerical simulations can only be preformed on one set of initial and boundary conditions at a time. We derived a non-dimensional expansion parameter from an approximate analytical solution and generalized it using an experimentally validated numerical solution, uncovering a non-dimensional behavior, which allows for rapid calculation of critical properties. Such properties could be used to rapidly calculate changes in fluid velocity, shear force, or fluid pressure due to microvessel expansion, without the need for complex analytical or numerical solutions. In order to validate our findings, we used high-resolution confocal images of diabetic retinas and observed that microaneurysms above our critical threshold demonstrated a dramatic, size-dependent increase in von Willebrand Factor (vWF) expression, a marker of endothelial dysfunction.

Materials and Methods: Numerical simulations were performed using COMSOL multiphysics simulation platform v3.5A with a direct (PARADISO) linear system solver and extra fine mesh. The experimental validation of the numerical model was performed in microfluidic devices, which were fabricated by soft lithography at the Harvey Krueger Center of Nanoscience and Nanotechnology at the Hebrew University of Jerusalem. Postmortem donor eyes from diabetic patients with early retinopathy characterized by the presence of microaneurysms were obtained from the National Disease Research Interchange (Philadelphia, USA). Retinas were examined from the vitreous surface using Biorad MRC 600 confocal laser scanning attachment mounted on a Zeiss Axiovert microscope using a 25 mW argon laser (Ion Laser Technology). Maximum projection images were analyzed using the Image J software (NIH) to quantifying microaneurysm geometry and average vWF intensity.

Results and Discussion: Endothelial dysfunction occurs when shear force drops below 0.4 Pa, enabling us to calculate a critical non-dimensional expansion ε of 0.38. Our analysis sets a critical aneurysm diameter of 15 μm for capillaries, 25 μm for venules and 104 μm for arterioles, above which endothelial dysfunction is predicted to occur. To test this hypothesis we obtained high-resolution confocal images of human diabetic retinas and quantified microaneurysm’s size distribution. The percentage of microaneurysms above our threshold ranged from 10% to 60%. Remarkably, while vWF expression in microaneurysms below our threshold was not significantly different than the surrounding microvasculature (p=0.076), it was 60±10% lower in microaneurysms above our threshold (p=7×10^-15).

 In contrast to the high correlation between vWF to the non-dimensional expansion, there was a weak correlation with the aneurysm size (R2=0.59).  The rapid advance of optics over the past decade permits high-resolution imaging of the retina in vivo with functional markers, such as vWF. A combined imaging of structure and function can lead to optimization and customization of preventive treatment before the onset of retinal edema. Our method will allow experts to identify and treat microaneurysms posing a high-risk of leakage, prior to edema, minimizing damage and saving vision.

Conclusions: Our approach has been to gain a critical understanding of the fluid dynamics in retinal microaneurysms, which will enable us to predict the risk associated with the diseased morphology by uncovering a non-dimensional behavior, allowing rapid calculation of critical propermmmDa sdsdly LE in the quarter i while tified  ties.