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: 10002238
• 负责人: REX A MOATS
• 金额: $ 40.5万
• 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 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10002238
• 关键词: Affect; Age; Aging; Animal Model; Animals; Area; Biophysics; Blindness; Bolus Infusion; Characteristics; Chemicals; Convection; Coupled; Data; Deposition; Diffusion; Drug Delivery Systems; Drug Transport; Effectiveness; Elderly; Equation; Evaluation; Eye; Fluorescence; Gel; Heterogeneity; Human; Humor; Implant; Individual; Investigation; Least-Squares Analysis; Life; Liquid substance; Location; Magnetic Resonance Imaging; Measurement; Measures; Mechanics; Membrane; Methods; Modeling; Ophthalmology; Outcome; Outcomes Research; Particulate; Particulate Matter; Permeability; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Physics; Physiological; Physiological Processes; Physiology; Process; Protocols documentation; Research; Retina; Retinal Diseases; Specific qualifier value; System; Techniques; Testing; Transport Process; Visualization; Vitreous humor; Work; age related; base; biophysical properties; design; drug distribution; experience; experimental study; fluid flow; follow-up; in vivo; macromolecule; mathematical analysis; mathematical model; nanoparticle; nanoparticulate; particle; predictive modeling; 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 这项工作的重点在于对毒品的运输的建模和分析 通过视网膜的玻璃幽默。视网膜疾病是盲目的常见原因之一 在老年人中，必须采用有效有效的药物分娩方法 开发视网膜。为了最大程度地减少对不希望的位置的药物分布，玻璃体内递送，尤其是 随着植入物的使用，已获得突出。在这方面，对眼睛有透彻的理解 运输过程是必要的，也是眼动动力学的综合数学模型 并应用视网膜药物输送的运输现象将是一个主要的积极步骤。之中 挑战包括了解MAC分子和颗粒药的运输以及 随着年龄的增长，玻璃体的部分液化（Synersis）的影响。具体目的包括： 1。眼输运参数的数学分析和测量。为了利用 现实生活中药物输送的数学模型，与流体流和药物有关的生物学参数 需要准确确定各种药物类型的运输。例如，这些包括 玻璃体幽默的扩散系数，玻璃体周围的膜的渗透性和 障碍评估大分子和颗粒在玻璃体中的经历。我们将执行此 借助已知的科学技术以及我们最近开发的新方法。 2。眼流体动力学和运输：具有鉴别的综合数学模型。 任务1中将进行的测量将以需要的数学模型实现 系统中生理上天然流体的各种运输过程以及干预 药物，渗透到视网膜区域。相关的传输方程将解决 通过仔细的实验​​进行计算和验证（任务3）。该模型将用于提供 药物输送率与药物沉积，药物类型，眼形的位置的关系（程度 液化和位置）和眼睛的其他传输参数。 3。通过实验验证建模和分析。数学模型的应用 将在动物模型中使用持续释放的大分子植入物进行玻璃体内递送。 在任务1中将确定必要的生物物理特性。 通过各种可能的眼形构图机械地创建（避免化学物质）到不同的水平。 根据药物类型和交货，将通过确定所需的交货水平的确定。 方法。为了克服模型和实验数据之间的潜在问题，我们将开始动物 在第二年初进行模型实验，以及离体实验，以修改和 验证我们的模型。

项目成果

Mathematical Model of Macromolecular Drug Transport in a Partially Liquefied Vitreous Humor.

部分液化玻璃体液中大分子药物转运的数学模型。

• DOI: 10.1115/1.4053197
• 发表时间: 2022
• 期刊: Journal of heat transfer
• 作者: Khoobyar,Anahid;Penkova,AnitaN;Humayun,MarkS;Sadhal,SatwindarSingh
• 通讯作者: Sadhal,SatwindarSingh

Mass diffusion coefficient measurement for vitreous humor using FEM and MRI.

使用 FEM 和 MRI 测量玻璃体液的质量扩散系数。

• DOI: 10.1088/1757-899x/297/1/012024
• 发表时间: 2018
• 期刊: IOP conference series. Materials science and engineering
• 作者: Rattanakijsuntorn,Komsan;Penkova,Anita;Sadhal,SatwindarS
• 通讯作者: Sadhal,SatwindarS

Diffusive Transport in the Vitreous Humor: Experimental and Analytical Studies.

玻璃体液中的扩散传输：实验和分析研究。

• DOI: 10.1115/1.4042297
• 发表时间: 2019
• 期刊: Journal of heat transfer
• 作者: Penkova,Anita;Moats,Rex;Humayun,MarkS;Fraser,Scott;Sadhal,SatwindarSingh
• 通讯作者: Sadhal,SatwindarSingh

Analytical and Computational Modeling of Sustained-Release Drug Implants in the Vitreous Humor.

玻璃体液中缓释药物植入物的分析和计算模型。

• DOI: 10.1115/1.4051785
• 发表时间: 2021
• 期刊: Journal of heat transfer
• 作者: Khoobyar,Anahid;Naghdloo,Amin;Penkova,AnitaN;Humayun,MarkS;Sadhal,SatwindarSingh
• 通讯作者: Sadhal,SatwindarSingh