Abstract
Purpose :
Retinal neovascular tufts, irregular vascular formations at the retinal-vitreous interface, threaten vision in neovascular retinal diseases such as diabetic retinopathy and retinopathy of prematurity (ROP). The current standard of care involves intravitreal administration of anti-VEGF antibodies to impede the bioavailability of VEGF, a presumed stimulant of tuft formation. However, the short half-life of these antibodies underscores the need for alternative therapeutic strategies. An improved understanding of the intricate interplay between the mechanical and biochemical processes driving tuft formation may offer novel treatment approaches.
Methods :
To mathematically interrogate the interplay between mechanical and biochemical factors, we developed a hybrid multicellular model of retinal neovascular tuft formation during oxygen-induced retinopathy (OIR). Endothelial cells, pericytes and microglia were described as agents, and signalling factors, such as VEGF, were described using differential equations. Cellular migration was driven by local cellular interactions, signalling factors and mechanical forces influenced by the stiffness of the environment. Simulation results were compared to literature OIR data.
Results :
The mathematical framework developed in this study accurately replicated small multicellular tuft structures. Our model suggests VEGF saturation and accumulation in the vitreous disrupts directional endothelial cell movement. The differential tissue density made entry into the vitreous more accessible than downward migration. Following extension into the vitreous, endothelial cell mechanics were altered by the compliant local surroundings, prompting aggregation. The relative importance weighted to mechanical forces and VEGF signalling was a key determinant of tuft formation. As the timing of treatment during ROP is critical, we used this model to show that optimised cycling of VEGF concentration (emulating intermittent oxygen therapy or anti-VEGF therapy) reduces the probability of tuft formation.
Conclusions :
The modelling results presented in this study support the theory that retinal neovascular tuft development is initially driven by pathologically high VEGF concentrations and is perpetuated by the low mechanical tension of the vitreous humor. Additional tests using this model advocate for the optimised cyclic regulation of retinal VEGF production.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.