Synthesis, Characterization and Biocompatibility of Hydrogel Vitreous Substitutes

水凝胶玻璃体替代品的合成、表征和生物相容性

• 批准号: 8394329
• 负责人: Nathan RAVI
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8394329
• 关键词: Acrylamides; Acrylates; Address; Age related macular degeneration; Aging; Air; Behavior; Biocompatible; Biological Assay; Biometry; Biomimetics; Blast Cell; Cataract; Cell Adhesion Inhibition; Cell Adhesion Molecules; Cell Death; Cell Line; Cell Proliferation; Cells; Characteristics; Clinical Trials; Communities; Crosslinker; Cystamine; Diabetes Mellitus; Diabetic Retinopathy; Disease; Disulfides; Drug Formulations; Elderly; Electroretinography; Engineering; Eye; Eye Injuries; Eye Movements; Face; Fluorocarbons; Future; Gases; Gel; Germ Cells; Glaucoma; Goals; Health; Histopathology; Hydrogels; In Situ; In Vitro; Individual; Inferior; Knowledge; Life; Liquid substance; Marketing; Measures; Mechanics; Medical; Membrane; Methods; Modeling; Monitor; Operative Surgical Procedures; Ophthalmology; Optics; Oryctolagus cuniculus; Osmotic Pressure; Outcome; Patients; Physiologic Intraocular Pressure; Physiological; Polymers; Population; Positioning Attribute; Postoperative Period; Process; Proliferative Vitreoretinopathy; Property; Prosthesis; Recovery; Recovery of Function; Refractive Errors; Rehabilitation Outcome; Rehabilitation therapy; Research; Retina; Retinal; Retinal Detachment; Retinal Perforations; Retinopathy of Prematurity; Risk; Science; Side; Silicone Oils; Silicones; Sodium; Soldier; Solutions; Swelling; Technology; Testing; Time; Toxic effect; Translating; Trauma; Veterans; Vietnam; Visual; Vitrectomy; Vitreous Hemorrhage; War; World War II; acrylic acid; aqueous; biomaterial compatibility; clinical practice; condensed matter physics; copolymer; crosslink; design; economic cost; efficacy testing; evidence base; experience; improved; in vivo; injured; interest; macula; novel; physical property; public health relevance; repaired; research study; tissue culture; viscoelasticity

DESCRIPTION (provided by applicant): Vitreous-associated disorders are numerous and include age-related macular degeneration, proli- ferative diabetic retinopathy, and retinopathy of prematurity. Ocular and orbital trauma resulting in vitreous hemorrhage, proliferative vitreoretinopathy (PVR) and retinal detachment is the most frequent eye-related problem encountered by our soldiers involved in modern warfare. Vitreoretinal surgery has made significant advances in the treatment of these problems with pars plana vitrectomies (PPV) being an essential part of this advancement. Presently used vitreous substitutes are neither physiological nor free from complications. Often, the rehabilitation process is long and requires multiple surgeries. This proposal addresses this critical problem by utilizing knowledge gained from engineering, ophthalmology, and soft-condensed matter physics. A more physiological vitreous prosthesis has been invented that mimics the natural vitreous in its mechanical, swelling, physical, and optical properties. This novel prosthesis employs a reversible disulfide crosslinker that enables it to be easily injected as a liquid into the vitreous cavity wherein it rapidly forms a viscoelastic hydrogel under physiological conditions. Preliminary studies in rabbits of one week duration have shown that poly(acrylamide) hydrogels were biocompatible and had no complications. In this study, the proposed vitreous prosthesis will be further developed using a copolymer of poly(acrylamide-sodium acrylate-acryloylphosphorlycholine [2-APC]). Sodium acrylate improves the optical characteristics, provides further tuning of swelling properties, and enhances long-term storage stability. 2-APC is known to inhibit protein and cell adhesion. The specific aims are to use statistically designed experiments to: 1) synthesize and characterize a set of 33 copolymers containing 5-15% sodium acrylate and/or 5-15% 2-APC. These copolymers will be chemically reduced to linear polymers, purified, characterized, and re-oxidized into hydrogels at 1.25-1.75 w/w%. The optical, physical, and mechanical properties of these hydrogels will be analyzed; 2) determine the predicted and experimentally measured osmotic pressure; and 3) rigorously test the biocompatibility of these prostheses in tissue culture and test the three most promising candidates in rabbits for periods of one week and three months. In the final year of the proposal, rabbits that have induced PVR will be tested for the efficacy of one of the hydrogel vitreous prosthetics in addressing PVR. The expected proposed outcome is a permanent biomimetic vitreous prosthesis that will decrease postoperative discomfort, tamponade the retina, and improve surgical rehabilitation outcomes when used in the battlefield or in situations applicable to our elderly population of veterans. The ophthalmic community (ARVO) and ophthalmic companies have expressed great interest in our materials and technology as a vitreous prosthesis. The market for vitreous substitutes is valued at over $100 million. PUBLIC HEALTH RELEVANCE: Vitreous-associated disorders are numerous and include age-related macular degeneration and pro- liferative diabetic retinopathy. Ocular and orbital traumas are an increasing problem encountered by our veterans and soldiers involved in modern warfare. Vitreous hemorrhage and retinal detachment are com- mon complications of trauma and these diseases. Currently used vitreous substitutes are neither physiolog- ical nor free from complications, which include glaucoma and cataracts as well as the necessity for multiple ocular surgeries. Preliminary studies have resulted in a biomimetic vitreous prosthesis that when injected as an aqueous solution, forms a gel like the natural vitreous in the ocular cavity. In this proposal, we will optimize the formulation of this prosthesis. The proposed prosthesis would be able to tamponade the reti- na, eliminate the need for multiple ocular surgeries, reduce recovery time for patients, and thus improve visual rehabilitation outcomes when used to treat our veterans or soldiers in the battlefield.

描述（由申请人提供）： 玻璃体相关疾病有很多，包括年龄相关性黄斑变性、增殖性糖尿病视网膜病变和早产儿视网膜病变。导致玻璃体出血、增殖性玻璃体视网膜病变（PVR）和视网膜脱离的眼部和眼眶外伤是参与现代战争的我们的士兵遇到的最常见的与眼部相关的问题。玻璃体视网膜手术在治疗这些问题方面取得了重大进展，平坦部玻璃体切除术（PPV）是这一进展的重要组成部分。目前使用的玻璃体替代物既不是生理性的，也没有并发症。通常，康复过程很长并且需要多次手术。该提案通过利用从工程学、眼科学和软凝聚态物理学中获得的知识来解决这个关键问题。一种更符合生理学的玻璃体假体已经被发明，它在机械、膨胀、物理和光学特性方面模仿天然玻璃体。这种新型假体采用可逆二硫化物交联剂，使其能够以液体形式轻松注入玻璃体腔，在生理条件下快速形成粘弹性水凝胶。对兔子进行为期一周的初步研究表明，聚（丙烯酰胺）水凝胶具有生物相容性，并且没有并发症。在这项研究中，所提出的玻璃体假体将使用聚（丙烯酰胺-丙烯酸钠-丙烯酰磷酸胆碱[2-APC]）的共聚物进一步开发。丙烯酸钠可改善光学特性，进一步调节溶胀性能，并增强长期储存稳定性。已知 2-APC 可以抑制蛋白质和细胞粘附。具体目标是使用统计设计的实验来：1）合成并表征一组包含 5-15% 丙烯酸钠和/或 5-15% 2-APC 的 33 种共聚物。这些共聚物将被化学还原为线性聚合物，纯化，表征，并重新氧化成 1.25-1.75 w/w% 的水凝胶。将分析这些水凝胶的光学、物理和机械性能； 2) 确定预测和实验测量的渗透压； 3）在组织培养中严格测试这些假体的生物相容性，并在兔子身上测试三种最有希望的候选物，为期一周和三个月。在该提案的最后一年，将测试诱导 PVR 的兔子，以确定其中一种水凝胶玻璃体假体在解决 PVR 方面的功效。预期的建议结果是一种永久性仿生玻璃体假体，当在战场或适用于我们老年退伍军人的情况下使用时，它将减少术后不适，填塞视网膜，并改善手术康复结果。眼科界 (ARVO) 和眼科公司对我们的玻璃体假体材料和技术表现出极大的兴趣。玻璃体替代品的市场价值超过 1 亿美元。 公共卫生相关性： 玻璃体相关疾病有很多，包括年龄相关性黄斑变性和增殖性糖尿病视网膜病变。眼部和眼眶外伤是参与现代战争的退伍军人和士兵遇到的一个日益严重的问题。玻璃体出血和视网膜脱离是外伤和这些疾病的常见并发症。目前使用的玻璃体替代物既不符合生理学要求，也存在并发症，包括青光眼和白内障，以及需要进行多次眼科手术。初步研究已经开发出了一种仿生玻璃体假体，当以水溶液形式注射时，它会形成类似于眼腔中天然玻璃体的凝胶。在本提案中，我们将优化该假体的配方。所提出的假体将能够填塞视网膜，消除多次眼部手术的需要，减少患者的恢复时间，从而在用于治疗战场上的退伍军人或士兵时改善视力康复结果。