Synthesis, Characterization and Biocompatibility of Hydrogel Vitreous Substitutes

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。眼外伤导致的玻璃体出血、增生性玻璃体视网膜病变（PVR）和视网膜脱离是现代战争中我军士兵最常见的眼部问题。玻璃体视网膜手术在这些问题的治疗方面取得了重大进展，其中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，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一关键问题。已经发明了一种更加生理学的玻璃体假体，其在机械、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的二硫化物交联剂，使其能够容易地作为液体注射到玻璃体腔中，其中其在生理条件下快速形成粘弹性水凝胶。在兔子中进行的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，提出的玻璃体假体将进一步开发使用的共聚物（丙烯酰胺-丙烯酸钠-丙烯酰磷酸胆碱[2-APC]）。丙烯酸钠改善了光学特性，提供了进一步的调节溶胀性能，并提高了长期储存稳定性。2-已知APC抑制蛋白质和细胞粘附。具体目的是使用统计学设计的实验来：1）合成和表征一组含有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成线性聚合物，纯化，表征，并以1.25-1.75 w/w%再氧化成水凝胶。将分析这些水凝胶的光学、物理和机械特性; 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，将对诱导PVR的兔子进行测试，以确定其中一种水凝胶玻璃体假体在解决PVR方面的有效性。预期的拟议结果是一种永久性仿生玻璃体假体，将减少术后不适，填塞视网膜，并改善手术康复结果时，在战场上使用或在适用于我们的老年退伍军人人口的情况。眼科界（ARVO）和眼科公司对我们的材料和技术作为玻璃体假体表现出极大的兴趣。玻璃替代品的市场价值超过1亿美元。

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.