Development of a Biomimetic Vitreous Substitute

描述（由申请人提供）：手术切除玻璃体并用代用品替代玻璃体已成为最常见的眼后段手术。目前的替代品虽然有功能，但都是暂时的，要么被吸收（气体），要么需要二次手术去除（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再脱离。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理解，然后利用这些信息来开发更多的生理玻璃体替代品，这些替代品可以施加渗透压来填塞视网膜。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（玻璃体的两个主要成分）的水溶性巯基化合成类似物来实现这一目标。在我们的具体目标中，我们将用去酰化的结冷胶代替胶原蛋白，而透明质酸将用甲基丙烯酰胺/甲基丙烯酸钠共聚物代替。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、光散射光谱和流变学来表征。计算和大分子模拟技术将被用于研究天然玻璃体的结构和力学性能之间的关系。我们的期望是，该技术将使我们能够利用光在体内建立玻璃体的三维分子剖面

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.