Development and application of a high-fidelity computational model of diabetic retinopathy hemodynamics: Coupling single-cell biophysics with retinal vascular network topology and complexity

糖尿病视网膜病变的发病机制是以视网膜形态异常为特征的。 视网膜毛细血管。虽然这种异常被用于疾病严重程度的临床评估， 其发生和发展的血流动力学机制尚不清楚。这些 形态异常高度局限于视网膜血管网络的特定区域，并可能 与血流动力学参数和力的局部变化相关。糖尿病病情显著 改变血细胞的生物物理性质，然而这种改变的生物物理性质的影响 对视网膜血流动力学和视网膜病变的发病机制尚不清楚。现有的活体成像 在拓扑结构复杂和多血管病变的血流动力学测量方面，技术存在局限性。 视网膜神经丛血管系统。此外，组织缺氧和血流自动调节功能丧失也是致病因素。 视网膜病变的因素。目前还没有研究表明糖尿病引起的个体生物物理改变 血细胞对视网膜组织氧合的丧失和血流的调节。我们的基本假设是：(I) 糖尿病红细胞(RBC)的生物物理学改变本身就可以通过改变 血流动力学参数和作用力；以及(Ii)这种变化在整个视网膜空间上是不均匀的 血管网络，并与血管异常的局灶性和异质性相关。《博大》 本项目的目的是了解糖尿病患者血液动力学与血液动力学的关系， 视网膜血管网络的拓扑结构，以及视网膜病变的发病机制，使用高保真、可预测 计算建模研究。具体目标是：1)开发一个多尺度的计算模型 糖尿病视网膜病变血流动力学，考虑精确的微结构和几何细节 从人体视网膜的活体图像中获得的3D血管网络，以及每个 代表糖尿病情况的生物物理性质改变的单个血细胞。2)预测糖尿病 RBC介导的视网膜血流动力学改变，以及这种改变与视网膜形成的关系 不同进展期微血管异常和血管适应的异质性 视网膜病变。3)评价不同细胞尺度血流动力学途径的意义。4)至 预测红细胞血流动力学在视网膜缺氧和一氧化氮生物利用度丧失中的作用 视网膜病变的因素。这项研究具有重要意义和创新性，因为它将(I)开发出第一个高保真， 一种结合了超大规模和多丛的精确3D几何的预测计算模型 硅视网膜血管系统，以及每个血细胞的3D变形和流变学，(Ii)提供流变学- 拓扑耦合机制是血流动力学介导的血管发生和发展的基础 异常，(Ii)直接模拟单个细胞-细胞和细胞-内皮细胞的异型相互作用，以及(Iv) 将个体红细胞瞬时变形与血液和视网膜组织气体运输结合起来。

Pathogenesis of diabetic retinopathy is characterized by the appearance of morphological abnormalities in the retinal capillary vessels. Although such abnormalities are used in the clinical evaluation of the disease severity, the hemodynamic mechanisms underlying their development and progression remain unknown. These morphological abnormalities are highly localized in specific regions of the retinal vascular network, and may correlate with the local variations of the hemodynamic parameters and forces. Diabetic conditions significantly alter the biophysical properties of the blood cells, however the influence of such altered biophysical properties on the retinal hemodynamics and pathogenesis of retinopathy are not known. Existing in vivo imaging techniques have limitations in terms of the hemodynamic measurements in the topologically complex and multi- plexus retinal vasculature. Additionally, tissue hypoxia and the loss of blood flow autoregulation are pathogenic factors in retinopathy. No study exists that correlates diabetes-mediated altered biophysics of the individual blood cell to the loss of retinal tissue oxygenation and flow regulation. Our underlying hypotheses are: (i) altered biophysics of diabetic red blood cells (RBC) alone can mediate vascular abnormalities by altering the hemodynamic parameters and forces; and (ii) such changes are spatially heterogeneous across the retinal vascular network, and correlate with the focal and heterogeneous nature of vascular abnormalities. The broad objective of this project is to understand the relationship between the hemodynamics of diabetic blood cells, retinal vascular network topology, and pathogenesis of retinopathy, using a high-fidelity, predictive computational modeling study. Specific aims are: 1) To develop a multiscale computational model of the diabetic retinopathy hemodynamics taking into consideration the precise microstructural and geometric details of the 3D vascular networks as obtained from in vivo images of the human retina, and 3D deformation of every single blood cell with altered biophysical properties representing diabetic conditions. 2) To predict diabetic RBC-mediated alteration in the retinal hemodynamics, and how such changes are correlated to the formation and heterogeneity of microvascular abnormalities and vascular adaptation at different stages of progressive retinopathy. 3) To evaluate the significance of diverse cellular-scale hemodynamic pathways involved. 4) To predict the role of RBC hemodynamics on retinal hypoxia and loss of nitric oxide bioavailability as pathogenic factors in retinopathy. This study is significant and innovative because it will (i) develop the first high-fidelity, predictive computational model that combines the exact 3D geometry of ultra-large-scale and multi-plexus in silico retinal vasculature, and 3D deformation and rheology of every blood cell, (ii) provide a rheology- topology coupling mechanism as a basis of hemodynamics-mediated initiation and progression of vascular abnormalities, (ii) directly model heterotypic individual cell-cell and cell-endothelium interactions, and (iv) couple individual RBC transient deformation with blood and retinal tissue gas transport.