CAREER: Nitric Oxide-Generating Polymers: Biofunctional Materials for the Prevention of Thrombosis and Restenosis

血管再狭窄是血管成形术和其他血管手术中常见的危及生命的并发症，用于重新开放闭塞的动脉。大约45%的血管成形术由于再狭窄而失败。再狭窄在很大程度上是由于动脉壁内平滑肌细胞的增殖和迁移形成了一层闭塞的组织，类似于疤痕组织。尽管血管再狭窄的机制尚不清楚，但很明显，血管损伤后的初始血栓形成起着重要作用，许多生长因子和细胞因子参与刺激平滑肌细胞的增殖、迁移和基质的产生。一氧化氮(NO)是由未受损伤的动脉内皮细胞产生的，其作用是限制平滑肌细胞的增殖，阻止血小板聚集，增加内皮细胞的增殖和迁移速度，并减弱白细胞的黏附。所有这些措施有望减少血管损伤后再狭窄的发生率和程度，例如血管成形性损伤。拟议的研究涉及开发在生理条件下产生NO的生物功能聚合物生物材料，这种材料可以通过光聚合在原位形成水凝胶，使人们能够在受损的动脉或心血管装置的表面覆盖一层薄薄的不产生NO的水凝胶。这些材料具有潜在的治疗血栓形成和再狭窄的潜力，并可作为一种新的工具来研究NO的细胞和分子作用，而不会产生全身影响。将合成两类NO释放聚合物，一类基于S-亚硝硫醇(可在数小时至数天内产生NO)，另一类基于NO/亲核络合物(可在数周至数月内产生NO)，聚乙二醇组成为生物相容性材料的主体，丙烯酸酯末端用于快速光聚合成水凝胶材料。这些新材料在防止血管平滑肌细胞增殖和刺激内皮细胞增殖方面的效果将通过培养的细胞进行评估。这项研究项目将为研究生、本科生和高中生提供动手培训，并将在体外平行平板血流装置中评估血小板聚集和血栓预防。这项提案涉及几个额外的教育目标。韦斯特博士将为本科生生物工程实验室课程开发一个新的生物材料模块：这门课程的设计将最大限度地将教学与研究结合起来，从而鼓励本科生以及更多的教职员工参与本科生的研究计划。参与上述项目的所有研究人员都将积极参与社区外展计划，包括访问当地公立高中，展示他们的研究成果，并教育社区了解生物工程的进展。

9875607WestRestenosis is a prevalent and life threatening complication of angioplasty and other vascular procedures used to re-open occluded arteries. Approximately 45% of all angioplasty procedures fail due to restenosis. Restenosis is due in large part to the proliferation and migration of smooth muscle cells to form of an occlusive layer of tissue, similar to scar tissue, within the arterial wall. Though the mechanisms of restenosis are as yet poorly understood, it is clear that initial thrombosis following vascular injury plays an important role and that numerous growth factors and cytokines are involved in stimulation of smooth muscle cell proliferation, migration, and matrix production. Nitric oxide (NO), produced by endothelial cells in uninjured arteries, acts to limit smooth muscle cell proliferation, prevent platelet aggregation, increase the rate of endothelial cell proliferation and migration, and attenuate leukocyte adhesion. All of these actions are expected to decrease the incidence and extent of restenosis after vascular injury, such as that caused by angioplasty.The proposed research involves the development of biofunctional polymeric biomaterials that produce NO under physiological conditions and that can be crosslinked via photopolymerization to form hydrogels in situ, allowing one to coat the surface of the damaged artery or a cardiovascular device with a thin layer of NO-producing hydrogel. The proposed materials have potential as a therapy for thrombosis and restenosis and as a novel tool to study the cellular and molecular actions of NO without systemic effects. Two classes of NO-releasing polymers will be synthesized, one based on S-nitrosothiols (which produce NO for hours to days) and another based on NO/nucleophile complexes (which produce NO for weeks to months), with polyethylene glycol (PEG) composing the bulk of the material for biocompatability and acrylate termini to allow rapid photopolymerization into hydrogel materials. The efficacy of these novel materials for the prevention of smooth muscle cell proliferation and the stimulation of endothelial cell proliferation will be assessed using cultured cells. Platelet aggregation will be assessed, and prevention of thrombosis will be evaluated in an ex vivo parallel plate blood flow assembly.This research project will provide hands-on training for graduate, undergraduate, and high school students. This proposal addresses several additional educational goals. Dr. West will develop a novel biomaterials module for the undergraduate bioengineering laboratory course: this course will be designed to maximize the integration of teaching with research and thus encourage undergraduate students, as well as more faculty members, to participate in the undergraduate research program. All of the researchers involved in the project described above will actively participate in community outreach programs, including visiting local public high schools to present their research and educate the community about advances in bioengineering.