Development of a Biomimetic Vitreous Substitute

仿生玻璃体替代品的开发

• 批准号: 8629747
• 负责人: Nathan RAVI
• 金额: $ 39.76万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629747
• 关键词: 3-Dimensional; Alkanes; Architecture; Biodegradation; Biological Assay; Biomimetics; Blindness; Cataract; Cell Line; Circular Dichroism; Clinical; Clinical Trials; Collagen; Complex; Cornea; Data; Development; Disease; Disulfides; Drug Delivery Systems; Drug Formulations; Engineering; Evaluation; Excision; Exposure to; Eye; Fibroblasts; Fluorocarbons; Fourier Transform; Future; Gases; Gel; Glaucoma; Goals; Growth; Health; Hyaluronic Acid; Hydrogels; Hydrophobicity; Implant; In Vitro; Incidence; Inflammation; Injection of therapeutic agent; Intervention; Knowledge; Lead; Light-Scattering Spectroscopy; Literature; Mechanics; Methods; Mission; Modeling; Molecular; Molecular Profiling; Molecular Weight; Nature; Nuclear; Nuclear Magnetic Resonance; Operative Surgical Procedures; Ophthalmologic Surgical Procedures; Optics; Oryctolagus cuniculus; Osmotic Pressure; Outcome; Oxygen; Patients; Pharmacotherapy; Physics; Physiological; Physiology; Play; Polymers; Polysaccharides; Prevention; Property; Public Health; Refractive Errors; Research; Resistance; Retina; Retinal; Retinal Detachment; Rheology; Role; Side; Silicone Oils; Sodium; Sodium Chloride; Solutions; Structure; Sulfhydryl Compounds; Surgical complication; System; Techniques; Testing; Translating; United States National Institutes of Health; Vision; Vitrectomy; Water; analog; anterior chamber; aqueous; base; biomaterial compatibility; copolymer; crosslink; design; expectation; flexibility; gellan; improved; in vivo; innovation; light scattering; methacrylamide; novel strategies; organizational structure; outcome forecast; pressure; public health relevance; repaired; success; tissue culture; tool

DESCRIPTION (provided by applicant): Surgical removal of the vitreous and its replacement with substitutes has become the most common posterior segment eye surgery. Present substitutes, while functional, are temporary and are either absorbed (gases) or require secondary surgery for removal (silicone oils). Surgical complications include development of nuclear cataract, glaucoma, corneal decompensation, and retinal re-detachments. Our long-term objective is to deepen our understanding of the macromolecular organization of the vitreous components and then to use this information to develop more physiological vitreous substitutes that can exert an osmotic pressure to tamponade the retina. Our central hypothesis is that we can accomplish this by using water-soluble thiolated synthetic analogues of the collagen and hyaluronic acid, the two primary components of the vitreous. In our specific aims we will substitute collagen with deacylated gellan while hyaluronic acid will be substituted by a methacrylamide/sodium methacryate copolymer. Statistically designed polymers and their hydrogels will be characterized using nuclear magnetic resonance, Fourier transform infrared, raman, circular dichroism, and light- scattering spectroscopies, and rheology. Computational and macromolecular modeling techniques will be employed to study the relationship between the structure and mechanical properties of the natural vitreous. It is our expectation that the techniques will enable us to develop a 3-D molecular profile of the vitreous in vivo by using light scattering techniques. Vitreous substitutes will be further tested by using light scattering, tisse culture and one-month in vivo rabbit studies followed by examination of the implant and histological evaluation of the retina. Our goal is to generate optimal biomimetic formulations of vitreous substitutes to be potentially translated into clinical interventions. This contribution wll be significant because these physiological gel substitutes could lessen patient burden by eliminating the need for removal of the substitute by secondary surgery, eliminating refractive error, possibly lowering the incidence of glaucoma and cataract postvitrectomy, and reducing redetachment of the retina. They could also be used to study the molecular mechanism of vitreous liquefaction and for intravitreal drug delivery therapies. The proposed research is innovative because it focuses on understanding and mimicking the natural vitreous and utilizing recent advances in soft condensed matter physics. Our two-component system representing rigid collagen and flexible hyaluronic acid will be endowed with sticky thiol groups. After injection of material as an aqueous solution, the rigid component will instantaneously form a physical gel imbedding the flexible copolymer. Upon subsequent exposure to oxygen, the thiol groups in the two components will form disulfide cross-links, resulting in a permanent hydrogel capable of providing osmotic pressure to tamponade the retina.

描述（由申请人提供）：手术去除玻璃体及其用替代物的替代已成为最常见的后段眼科手术。 目前的替代品虽然功能是暂时的，并且被吸收（气体）或需要进行继发手术才能去除（硅油）。 手术并发症包括核白内障，青光眼，角膜代表性代理和视网膜重新结束的发展。 我们的长期目标是加深我们对玻璃体成分的大分子组织的理解，然后使用这些信息来开发更多的生理玻璃体替代物，这些玻璃体替代物可以施加渗透压以侵略视网膜。 我们的中心假设是，我们可以使用胶原蛋白和透明质酸的水溶性硫醇化合成类似物（玻璃体的两个主要成分）来实现这一目标。 在我们的具体目的中，我们将用脱酰化的凝胶凝胶代替胶原蛋白，而透明质酸将被甲基丙烯酰胺/甲基丙烯酸钠共聚物取代。 统计设计的聚合物及其水凝胶将使用核磁共振，傅立叶变换红外，拉曼，圆形二色性和光散射光谱和流变学来表征。 将采用计算和大分子建模技术来研究天然玻璃体的结构和机械性能之间的关系。 我们期望这些技术将使我们能够使用光在体内开发玻璃体的3-D分子剖面 散射技术。 玻璃体替代物将通过使用光散射，Tisse培养和一个月的体内兔研究进一步测试，然后检查视网膜的植入物和组织学评估。 我们的目标是生成玻璃体替代物的最佳仿生制剂，以便将其转化为临床干预措施。 这项贡献很重要，因为这些生理凝胶替代品可以通过消除次级手术去除替代品的需要来减轻患者负担，从而消除了屈光度误差，从而降低了青光眼和白内障后胃切除术的发生率，并减少了视网膜的重新训练。 它们还可以用于研究玻璃体液化的分子机制和玻璃体内药物递送疗法。 拟议的研究具有创新性，因为它专注于理解和模仿天然的玻璃体，并利用柔软的凝结物理学的最新进展。 我们代表刚性胶原蛋白和柔性透明质酸的两个组件系统将赋予粘性硫醇基团。 注入材料作为水溶液后，刚性成分将立即形成物理凝胶，嵌入柔性共聚物。 随后暴露于氧气后，这两个成分中的硫醇基团将形成二硫键交联，从而导致永久性水凝胶能够提供渗透压以淡化视网膜的淡化。