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

9875607西动脉狭窄是血管成形术和其他用于重新打开闭塞动脉的血管手术的常见且危及生命的并发症。大约45%的血管成形术因再狭窄而失败。再狭窄在很大程度上是由于平滑肌细胞增殖和迁移，形成闭塞的组织层，类似于疤痕组织，在动脉壁内。尽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了平滑肌细胞增殖、迁移和基质生成的刺激。一氧化氮（NO）由未损伤动脉内皮细胞产生，其作用是限制平滑肌细胞增殖，阻止血小板聚集，增加内皮细胞增殖和迁移速度，减弱白细胞粘附。所有这些作用都有望减少血管损伤后再狭窄的发生率和程度，如血管成形术引起的再狭窄。拟议的研究涉及生物功能高分子生物材料的开发，这种材料可以在生理条件下产生NO，并且可以通过光聚合交联在原位形成水凝胶，允许人们在受损动脉或心血管装置的表面涂上一层薄薄的NO产生水凝胶。所提出的材料具有治疗血栓和再狭窄的潜力，并可作为研究NO的细胞和分子作用而不产生全身效应的新工具。两类释放NO的聚合物将被合成，一种基于s -亚硝基硫醇（可以产生数小时到数天的NO），另一种基于NO/亲核复合物（可以产生数周到数月的NO），聚乙二醇（PEG）构成了生物相容性材料的主体，丙烯酸酯末端允许快速光聚合成水凝胶材料。这些新材料在防止平滑肌细胞增殖和刺激内皮细胞增殖方面的功效将通过培养细胞进行评估。血小板聚集将被评估，血栓形成的预防将在体外平行板血流组装中评估。这个研究项目将为研究生、本科生和高中生提供实践训练。这一建议涉及了几个额外的教育目标。韦斯特博士将为本科生物工程实验课程开发一种新的生物材料模块：这门课程的设计将最大限度地将教学与研究结合起来，从而鼓励本科生和更多的教师参与本科研究项目。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，并向社区介绍生物工程方面的进展。

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.