Mathematical Modeling and Analysis of Ocular Fluid Dynamics and Transport Phenomena for Retinal Drug Delivery

项目摘要 这项工作的重点是对眼睛的建模和分析与药物的运输 通过玻璃体液到达视网膜视网膜疾病是失明的常见原因之一- 在老年人中，针对老年人的高效和有效的药物递送方法至关重要。 视网膜发育。为了最小化药物分布到不期望的位置，玻璃体内递送，特别是 随着植入物的使用，已经变得突出。在这方面，深入了解眼 传输过程是必要的，和一个全面的数学模型的眼流体动力学 并且将转运现象应用于视网膜药物递送将是主要的积极步骤。之间 这些挑战包括理解大分子和颗粒药物的运输， 随着年龄的增长，玻璃体部分液化（脱水收缩）的影响。具体目标包括： 1.眼传输参数的数学分析与测量。为了利用 现实生活中的药物输送的数学模型，与流体流动和药物相关的生物物理参数 需要准确地确定各种药物类型的转运。这些措施包括，例如， 玻璃体的扩散系数，玻璃体周围膜的渗透性，以及 阻碍评价玻璃体中大分子和颗粒。我们将执行这一任务 用已知的科学技术，以及我们最近开发的新方法。 2.眼流体动力学和传输：综合数学模型与脱水收缩。 在任务1中进行的测量将在一个数学模型中实现， 生理天然流体在系统中的各种运输过程以及介入的 药物，再加上渗透到视网膜区域。相关的输运方程将被求解 通过计算和仔细的实验验证（任务3）。该模型将用于提供 作为药物沉积位置、药物类型、眼地形（程度） 液化和位置）和眼睛的其他传输参数。 3.将建模与分析与实验相结合。数学模型的应用 将在动物模型中使用缓释大分子植入物进行玻璃体内递送， 其必要的生物物理性质将在任务1中确定。脱水情况将是 机械地（避免化学品）产生不同的水平，具有各种可能的眼睛形貌。 随后将根据药物类型和交付情况确定所需的交付水平 法为了克服我们的模型和实验数据之间的潜在问题，我们将开始动物实验。 模型实验在第二年的早期，沿着离体实验，以便修改和 验证我们的模型。

Project Summary The focus of this work is on the modeling and analysis of the eye with regard to of the transport of drugs through the vitreous humor to the retina. With retinal diseases being one of the common causes of blind- ness amongst the elderly, it is imperative that efficient and effective drug-delivery methods targeting the retina be developed. To minimize drug distribution to undesired locations, intravitreal delivery, especially with the use of implants, has gained prominence. In this regard, a thorough understanding of the ocular transport processes is necessary, and a comprehensive mathematical model for the ocular fluid dynamics and transport phenomena with application to retinal drug delivery would be a major positive step. Among the challenges include understanding the transport of mac-romolecular and particulate drugs together with the effect of partial liquefaction (syneresis) of the vitreous with age. The specific aims include: 1. Mathematical Analysis and Measurement of Ocular Transport Parameters. In order utilize the mathematical model for real-life drug delivery, the biophyisical parameters relevant to fluid flow and drug transport need to be accurately determined for various drug types. These include, for example, the diffusion coefficient of the vitreouus humor, the permebility of the membranes around the vitreous, and the hindrance evaluation that large molecules and particles experience in the vitreous. We shall carry this out with the known scientific techniques, as well as the new methods that we have recently developed. 2. Ocular Fluid Dynamics and Transport: Comprehensive Mathematical Model with Syneresis. The measurements that will be made in Task 1 will be implemented in a mathematical model which entails the various transport processes of the physiologically natural fluids in the system as well the intervening drugs, coupled with permeation into the retinal region. The relevant transport equations will be solved computationally and validated with careful experimentation (Task 3). The model will be applied to provide drug delivery rates as a function of the location of drug deposition, drug type, the eye topography (degree of liquefaction and location) and other transport parameters of the eye. 3. Validate the Modeling and Analysis with Experiments. Applications of the mathematical model will be made for intravitreal delivery using sustained-release macrmolecular implants in animal models for which the requisite biophysical properties will have been determined in Task 1. Syneretic conditions will be created mechanically (avoiding chemicals) to different levels with a variety of possible eye topographies. This will be followed up with the determination of required delivery levels, based on drug type and delivery method. To overcome potential issues between our model and the experimental data, we will begin animal model experimentation early in the second year, along with the ex vivo experiments in order to modify and validate our model.