Design and Synthesis of Elastic Polymers for Use in Vascular Grafts

描述（由申请人提供）：小直径（<5 mm）血管移植物的成功率较低。这些器械的失效归因于移植物和天然血管之间的机械性能差异，以及合成材料无法支撑内皮单层。考虑到这些缺点，本提案的目的是设计和合成用于血管移植物的弹性和生物活性材料，其将具有长期功效。为了实现这一目标，材料将具备以下品质：（i）由一类新的官能化反式环辛烯单体组装的柔性烃主链（ii）通过基于弹性蛋白样肽序列的聚集起作用的嵌段共聚物或交联的聚合物网络而具有与天然血管相似的弹性（iii）含有促进内皮细胞选择性粘附的整联蛋白结合基序的配体。开环易位聚合（ROMP）已经作为允许高度控制聚合物的机械性质的独特方法出现。钌基开环易位聚合催化剂在极性官能团存在下表现出优异的活性，并已被用于合成具有令人印象深刻的生物活性成分的聚合物。因此，该方法的模块化允许获得各种聚合物支架，其中可以定制聚合物的弹性并且可以引入生物活性配体。提出了一组官能化反式环辛烯单体，其含有弹性蛋白序列Val-Pro-Gly-Val-Gly或其类似物，用于合成在水性环境中表现出强链间聚集效应的材料。聚合的条件，通过它的弹性可以通过改变嵌段尺寸进行调整。或者，将制备无规共聚物，其在聚合物链的末端含有用于交联以形成网络的反应性部分。网络的弹性和水含量可以通过改变交联之间的距离来调节。这些材料可能会对每年为事故、心血管疾病、糖尿病和其他疾病的受害者进行的数百万次手术产生巨大影响。公共卫生相关性小型和中型人造血管通常在不到六个月内失效，很少能持续两年以上。为了增加需要这些假体的患者的健康和寿命，本研究的目的是设计一种用于人工血管的新材料，以解决当前技术的不足。

DESCRIPTION (provided by applicant): Small diameter (<5 mm) vascular grafts exhibit low success rates. Failure of these devices has been attributed to the difference in mechanical properties between the graft and the natural vessel, and the inability of the synthetic material to support an endothelial monolayer. With these shortcomings in mind, the aim of this proposal is to design and synthesize an elastic and bioactive material for vascular grafts that will have long-term efficacy. In order to achieve this objective, the material will possess the following qualities: (i) a flexible hydrocarbon backbone assembled from a new class of functionalized trans-cyclooctene monomers (ii) elasticity similar to that of natural vessels through either block copolymers that function based on the aggregation of elastin-like peptide sequences or crosslinked polymer networks (iii) ligands containing an integrin binding motif that promotes selective adhesion of endothelial cells. Ring-opening metathesis polymerization (ROMP) has emerged as a unique method that allows for a high degree of control over a polymer's mechanical properties. Ruthenium catalysts for ROMP show excellent activity in the presence of polar functional groups and have been employed in the synthesis of polymers with impressive bioactive components. The modularity of the process thus allows for access to a variety of polymer scaffolds in which the elasticity of the polymer can be tailored and bioactive ligands can be introduced. A set of functionalized trans-cyclooctene monomers is proposed that contain either the elastin sequence Val-Pro-Gly-Val-Gly or an analog thereof for the synthesis of a material that exhibits strong interchain aggregation effects in an aqueous environment. Conditions for polymerization are presented through which the elasticity may be adjusted by varying block size. Alternatively, random copolymers will be made that contain reactive moieties at the termini of the polymer chain for crosslinking to form a network. The elasticity and water content of the network may be adjusted by varying the distance between crosslinks. These materials could have great impact on millions of surgeries that are performed every year on patients that are victims of accidents, cardiovascular disease, diabetes and other afflictions. PUBLIC HEALTH RELEVANCE Small and medium sized artificial blood vessels often fail in less than six months and rarely last beyond two years. In order to increase the health and lifetime of patients in need of these prostheses, the aim of this research is to design a new material for application in artificial blood vessels that addresses the deficiencies of the current technology.