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

视网膜药物输送的眼液动力学和传输现象的数学建模和分析

• 批准号: 9194233
• 负责人: REX A MOATS
• 金额: $ 38.11万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9194233
• 关键词: Affect; Age; Animal Model; Area; Blindness; Bolus Infusion; Characteristics; Chemicals; Convection; Coupled; Data; Deposition; Diffusion; Drug Delivery Systems; Drug Transport; Effectiveness; Elderly; Equation; Evaluation; Experimental Models; Eye; Fluorescence; Gel; Heterogeneity; Human; Humor; Imagery; Implant; Individual; Investigation; Least-Squares Analysis; Life; Liquid substance; Location; Magnetic Resonance Imaging; Measurement; Measures; Membrane; Methods; Modeling; Ophthalmology; Outcome; Outcomes Research; Particulate; Particulate Matter; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physics; Physiology; Process; Protocols documentation; Research; Retina; Retinal; Retinal Diseases; Specific qualifier value; System; Techniques; Testing; Transport Process; Vitreous humor; Work; age related; base; biophysical properties; design; drug distribution; experience; fluid flow; follow-up; in vivo; macromolecule; mathematical analysis; mathematical model; nanoparticle; nanoparticulate; particle; predictive modeling; research study; solute; theories

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.

项目摘要 这项工作的重点是关于药物运输的眼睛的建模和分析 通过玻璃体的体液进入视网膜。视网膜疾病是导致失明的常见原因之一- 在长者当中，必须以有效率和有效的药物输送方法针对长者 视网膜是发达的。为了最大限度地减少药物分布到不必要的位置，玻璃体内给药，尤其是 随着植入物的使用，已经获得了突出的地位。在这方面，透彻地了解眼睛 传输过程是必要的，并建立了一个全面的眼液动力学数学模型 而将转运现象应用于视网膜药物输送将是一个重要的积极步骤。其中 挑战包括了解大分子和微粒药物的运输以及 玻璃体的部分液化(脱水)随年龄的变化。具体目标包括： 1.眼部传输参数的数学分析与测量。为了利用 真实药物输送的数学模型，与流体流动和药物有关的生物物理参数 需要准确地确定各种药物类型的运输情况。其中包括，例如， 玻璃体液的扩散系数，玻璃体周围膜的渗透率，以及 大分子和大颗粒在玻璃体中所经历的阻碍评估。我们将执行这项任务。 利用已知的科学技术，以及我们最近开发的新方法。 2.眼部液体动力学与转运：综合数学模型。 将在任务1中进行的测量将在数学模型中实施，该数学模型需要 生理自然流体在系统中的各种输运过程及其介入性 药物，再加上渗入视网膜区域。相关的输运方程将被求解 通过计算并通过仔细的实验进行验证(任务3)。该模型将被应用于提供 药物释放率与药物沉积位置、药物类型、眼部地形(度数)有关 液化和位置)和眼睛的其他传输参数。 3.通过实验对建模和分析进行了验证。数学模型的应用 将使用缓释大分子植入物在动物模型中进行玻璃体内释放 哪些必要的生物物理性质将在任务1中确定。协同条件将是 机械制造(避免化学物质)到不同的水平，有各种可能的眼部地形。 随后将根据药物类型和给药情况确定所需的给药水平。 方法。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 第二年早期的模型实验，以及体外实验，以修改和 验证我们的模型。