Progression of Diabetic Capillary Occlusion: A Model

Abstract

An explanatory computational model is developed of the contiguous areas of retinal capillary loss which play a large role in diabetic maculapathy and diabetic retinal neovascularization. Strictly random leukocyte mediated capillary occlusion cannot explain the occurrence of large contiguous areas of retinal ischemia. Therefore occlusion of an individual capillary must increase the probability of occlusion of surrounding capillaries. A retinal perifoveal vascular sector as well as a peripheral retinal capillary network and a deleted hexagonal capillary network are modelled using Compucell3D. The perifoveal modelling produces a pattern of spreading capillary loss with associated macular edema. In the peripheral network, spreading ischemia results from the progressive loss of the ladder capillaries which connect peripheral arterioles and venules. System blood flow was elevated in the macular model before a later reduction in flow in cases with progression of capillary occlusions. Simulations differing only in initial vascular network structures but with identical dynamics for oxygen, growth factors and vascular occlusions, replicate key clinical observations of ischemia and macular edema in the posterior pole and ischemia in the retinal periphery. The simulation results also seem consistent with quantitative data on macular blood flow and qualitative data on venous oxygenation. One computational model applied to distinct capillary networks in different retinal regions yielded results comparable to clinical observations in those regions.

A Computational Model of Peripheral Photocoagulation for the Prevention of Progressive Diabetic Capillary Occlusion

“…This assumption allows us to remove a blood flow pathway permanently from the vascular network once occlusion occurs. As an extension to model assumptions in prior study [8], we further assume in the present study that photocoagulation burns are effectively diffusive sources of oxygen of a size and shape determined by a coagulation burn. We predict that photocoagulation burns of proper patterns and sizes, as oxygen sources, would oxygenate otherwise hypoxic Mueller cells, lowering their local synthesis of VEGF and thereby reduce the probability of adjacent capillary occlusion as this probability is dependent on local VEGF concentration.…”

“…Next, we apply a hemodynamic model [8] to calculate blood flow velocities across the whole vascular network (“flow velocity map in Figure 1(a)”). We then mathematically model oxygen advection within the vasculature, oxygen diffusion between vessels and cells, and oxygen consumption by Mueller cells and other retinal cells.…”

“…This paper introduces another rationale for panretinal photocoagulation with possible implications for therapy. Our previous modelling work [8] was on the progression of retinal ischemia due to an adverse local feedback cycle in which occlusion of a single retinal capillary increases the likelihood of occlusion of adjacent capillaries. This model was developed to explain the apparent inconsistency between a mechanism of individual capillary occlusion based on leukocyte adhesion and the large areas of contiguous capillary loss seen clinically as the dark areas on wide field fluorescein angiography.…”

“…These two alterations in the physiology of diabetes act as core mechanisms in the assumptions driving the model in discriminating the diabetic from the normal. While there is much physiological support for the noncanonical role of VEGF as a central factor in capillary occlusion acting through an elevation of endothelial ICAMs [8], in our model VEGF is regarded as a surrogate for the complex balance of it and various additional cytokines such as angiopoietin-2 and pigment epithelial derived factor. In our previous modelling study [8], we focused on treating diffusing VEGF as the important spatially propagating signal, which linked local capillary closure-induced retinal hypoxia with derived occlusion of adjacent capillaries.…”

“…While there is much physiological support for the noncanonical role of VEGF as a central factor in capillary occlusion acting through an elevation of endothelial ICAMs [8], in our model VEGF is regarded as a surrogate for the complex balance of it and various additional cytokines such as angiopoietin-2 and pigment epithelial derived factor. In our previous modelling study [8], we focused on treating diffusing VEGF as the important spatially propagating signal, which linked local capillary closure-induced retinal hypoxia with derived occlusion of adjacent capillaries. We ignored the mechanistic complexity of leukostasis involving various molecular factors and used occlusion probability function dependent on local blood flow velocity and VEGF level to describe the likelihood of emergence of capillary occlusion.…”