Design and Synthesis of Elastic Polymers for Use in Vascular Grafts

描述（由申请人提供）：小直径（< 5mm）血管移植成功率低。这些装置的失败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，本课题的目的是设计和合成一种具有长期疗效的弹性和生物活性的血管移植材料。为了实现这一目标，该材料将具有以下特性：(i)由一类新的功能化反式环烯单体组装而成的柔性碳氢化合物骨架；（ii）通过基于弹性蛋白样肽序列聚集或交联聚合物网络的嵌段共聚物具有与天然血管相似的弹性；（iii）含有整合素结合基序的配体，可促进内皮细胞的选择性粘附。开环复分解聚合（ROMP）是一种独特的方法，可以高度控制聚合物的机械性能。钌催化剂在极性官能团的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，该过程的模块化允许访问各种聚合物支架，其中聚合物的弹性可以定制，并且可以引入生物活性配体。提出了一组功能化的反式环烯单体，包含弹性蛋白序列Val-Pro-Gly-Val-Gly或类似物，用于合成在水环境中表现出强烈的链间聚集效应的材料。提出了聚合的条件，通过该条件可以通过改变块大小来调节弹性。或者，将制造随机共聚物，其在聚合物链的末端包含用于交联形成网络的活性基团。网络的弹性和含水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例手术产生重大影响。与公共卫生相关的中小型人造血管通常在不到6个月的时间内衰竭，很少能维持两年以上。为了提高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应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.