Mechanisms of macular oedema development and therapeutic response: An in-silico modelling study

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Abstract Purpose To investigate the interplay between biomechanics, fluid dynamics, and solute transport in Diabetic Macular Oedema (DMO) using a mechanics-based computational model, aiming to elucidate mechanisms behind variable treatment outcomes. Methods We developed a multiphysics model of the retina within a porous media framework. The model integrates OCT-derived geometry, vascular leakage, retinal biomechanics (including Müller cell fibre architecture), retinal pigment epithelium (RPE) function, and anti-VEGF transport. We simulated oedema development and therapeutic response by varying these parameters systematically. Results Model results showed that active RPE pumping is essential for maintaining retinal dehydration. Our simulations revealed a critical trade-off related to Müller cell architecture: the physiological ‘z-shaped’ orientation protects against oedema but impedes anti-VEGF drug delivery to leaky vessels. In contrast, a pathological, vertical Müller cell alignment increases oedema susceptibility but allows for a faster therapeutic response due to improved drug diffusion. Conclusions Müller cell orientation presents a trade-off between biomechanical protection and therapeutic efficacy, offering a novel mechanistic explanation for the variable patient responses to anti-VEGF therapy observed clinically. This in-silico framework is a powerful tool for dissecting DMO pathophysiology and has the potential to guide the development of personalised treatment strategies.

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