Development of a Biomimetic Vitreous Substitute

描述(申请人提供)：玻璃体切除手术和其替代物已成为最常见的后段眼科手术。目前的替代品虽然有功能，但都是暂时的，要么被吸收(气体)，要么需要二次手术才能取出(硅油)。手术并发症包括核性白内障、青光眼、角膜失代偿和视网膜脱离。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了解，然后利用这些信息开发更多的生理性玻璃体替代品，这种替代品可以施加渗透压来填充视网膜。我们的中心假设是，我们可以通过使用胶原蛋白和透明质酸这两种玻璃体的主要成分--水溶性的硫代合成类似物来实现这一点。在我们的特定目标中，我们将用脱酰化凝胶取代胶原蛋白，而用甲基丙烯酰胺/甲基丙烯酸钠共聚物取代透明质酸。统计设计的聚合物及其水凝胶将使用核磁共振、傅里叶变换红外、拉曼、圆二色谱、光散射光谱和流变学进行表征。计算和大分子模拟技术将被用来研究天然玻璃的结构和机械性能之间的关系。我们希望这项技术将使我们能够利用光在体内开发出玻璃体的三维分子轮廓 散射技术。玻璃体替代物将通过光散射、组织培养和一个月的活体兔子研究进一步测试，然后检查植入物和视网膜的组织学评估。我们的目标是产生玻璃体替代品的最佳仿生配方，以潜在地转化为临床干预措施。这一贡献将是显著的，因为这些生理凝胶替代品可以通过消除二次手术取出替代品的需要、消除屈光不正、可能降低玻璃体切除术后青光眼和白内障的发生率以及减少视网膜再脱离来减轻患者的负担。它们还可用于研究玻璃体液化的分子机制和玻璃体内给药治疗。这项拟议的研究具有创新性，因为它专注于理解和模拟天然玻璃体，并利用软凝聚态物理学的最新进展。我们的代表硬质胶原和弹性透明质酸的双组分系统将被赋予粘性硫醇基团。在将材料作为水溶液注入后，刚性组分将瞬间形成嵌入柔性共聚物的物理凝胶。当随后暴露在氧气中时，这两个组分中的硫醇基团将形成二硫键交联，从而产生一种能够提供渗透压以填充视网膜的永久性水凝胶。

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.