Increasing biocompatibility of stents through CD47 functionalization

描述（由申请人提供）：与血管内支架使用相关的病理生理学已得到充分记录，并且在接受该医疗器械的所有患者中观察到高达50%。不幸的是，一直缺乏创新的解决方案，以防止不利的影响，如支架内再狭窄和新生内膜形成，心血管支架部署。用生物活性治疗分子对医疗器械的血液接触表面进行生物功能化，将假设减弱在支架使用中观察到的异常血液相容性问题。CD47已被鉴定为免疫抑制受体SIRP的配体，并已被证明赋予异种移植红细胞和合成纳米颗粒的“自我”状态。Stanley J. Stachelek博士是该项目的共同主要研究者（PI）之一，也是开发解决心血管生物材料炎症反应策略的专家，他最近描述了一种平台技术，通过共价连接普遍表达的细胞表面蛋白CD47，聚合物的表面。补充Stachelek博士的专业知识，医学博士伊利亚菲什拜因，哲学博士、该项目的另一位共同主要研究者发表了大量关于开发新的创新策略以增强血管内支架生物相容性的文章。根据这两位研究者的专业知识，本提案将检验重组CD47可固定在血管内支架表面以减少支架展开后观察到的促血栓形成和促炎症事件的假设。该提案将有两个具体目标。在第一个目标中，研究人员将优化重组CD47与不锈钢表面的附着。将使用体外和离体方法进行额外的研究以表征CD47官能化金属表面的抗炎特性。然后将在第二个和最终特定目标中使用CD 47修饰的金属表面的铅制剂，其中将使用支架成形术的大鼠模型来评估CD 47修饰的支架在增强血液相容性和减少新生内膜形成和支架内再狭窄方面的有效性。该提案融合了心脏病学，合成化学，免疫学和材料科学的专业知识和概念，将有助于开发一种新颖的创新治疗策略，以解决心血管支架使用的异常影响。

DESCRIPTION (provided by applicant): The pathophysiology associated with endovascular stent usage is well documented and is observed in up to 50% of all patients receiving the medical device. Unfortunately there has been a paucity of innovative solutions to prevent the untoward effects, such as in-stent restenosis and neointimal formation, of cardiovascular stent deployment. Biofunctionalizing the blood-contacting surface of medical devices, with bioactive therapeutic molecules, would hypothetically attenuate the aberrant hemocompatibility issues that are observed in stent usage. CD47 has been identified as a ligand for the immune inhibitory receptor SIRP¿ and has been shown to confer "self" status on xenotransplanted red blood cells and synthetic nanoparticles. Dr. Stanley J. Stachelek, one of this project's co-Principle Investigator (PI) and an expert on developing strategies to address the inflammatory response to cardiovascular biomaterials, has recently described a platform technology to reduce the inflammatory response to a range of biomaterials such as polyvinyl chloride (PVC) and polyurethane (PU), by covalently linking a ubiquitously expressed cell surface protein, CD47, to the polymers' surface. Complementing Dr. Stachelek's expertise, Dr. Ilia Fishbein, M.D., Ph.D., the other co-PI on the project, has published extensively on developing new and innovative strategies to enhance endovascular stent biocompatibility. Drawing from the expertise of these two investigators, this proposal will test the hypothesis that recombinant CD47 can be immobilized onto the surface of endovascular stents to decrease the pro-thrombotic and pro-inflammatory events that are observed after stent deployment. The proposal will have two Specific Aims. In the first aim, the investigators will optimize the attachment of recombinant CD47 to stainless steel surfaces. Additional studies will be performed to characterize, using in vitro and ex vivo methodologies, the anti-inflammatory properties of CD47 functionalized metal surfaces. Lead formulations of CD47 modified metal surfaces will then be used in the second and final Specific Aim where a rat model of stenting angioplasty will be used to assess the efficacy of CD47 modified stents in enhancing hemocompatibility and reducing neointimal formation and in-stent restenosis. This proposal, which blends expertise and concepts from cardiology, synthetic chemistry, immunology, and materials science will contribute to developing a novel and innovative therapeutic strategy to address the aberrant effects of cardiovascular stent usage.