Mitigation of stent-mediated pathology by streamlined geometry

描述（由申请人提供）：药物洗脱支架（DES）用于物理性重新打开冠状动脉狭窄区域，以恢复心脏血流，并通过长期释放抗增殖药物抑制再狭窄。然而，2006年报告了局部迟发性炎症和晚期支架内血栓形成（LST）的显著发生率，导致在展开后数月至数年内发病和死亡。这些警告提醒FDA重新考虑DES的安全性并发布安全警告。由于DES抑制再狭窄，支架支柱保持在动脉表面与流动的血液无限期接触，而不是被新生内膜迅速过度生长。尽管平均高度仅为1005 m，但支柱显著改变了局部流动特性，从而在支架支柱附近区域形成包含不稳定涡流的流动分离区。这些涡流的特征在于血液流速显著低于整体流速和延长的颗粒停留时间。我们提出，流动分离区域代表微反应室，其中来自血液和血管壁的促凝血和促炎元素积累。此外，支架区域的再内皮化被分离区的低剪切应力抑制，从而促成促病理环境。从冠状动脉血流的数值模拟和我们对动脉几何形状的广泛血液动力学研究（其中自然血流扰动（如不稳定涡流）诱导促病理血管细胞表型）中学习，我们假设支架支柱几何形状导致局部促血栓形成和促炎症环境。这项R21研究资助提出了地形解决方案，以减轻或消除这些后果，并在体外受控条件下通过实验对其进行测试，这是体内实验之前的一组必要的原理验证探索性研究。在基本流体动力学原理的指导下，CFD数值模拟确定了一系列流线型支架支柱几何形状，可最大限度地减少或消除流动分离。目标1将使用粒子图像测速法来表征模拟冠状动脉血流的细胞培养流动室中和按比例缩放至可管理的全血量的流管中不同制造的支柱支架几何形状的流场。目的2将测试在有利于血栓形成的化学和基质环境中，相应支柱设计对活化血小板沉积和血栓生长特征的影响。最后，目标3将评价重新设计的支架对再内皮化和内皮的凝血相关分子表型表达的影响。该提案通过探索支架重新设计的潜在高效用来解决重要临床问题的机制，并建立在我们在血液动力学，生物医学工程和血管细胞和分子病理学方面的丰富经验基础上。流线型支柱设计的相同原则也适用于BMS，其中与血管表面支架物理存在相关的血栓形成发生较早，在新生内膜形成之前。公共卫生相关性：冠状动脉支架是心绞痛和心脏病发作的常见且有效的治疗方法，特别是当金属支架涂覆有抑制组织反应驱动的动脉再闭合（再狭窄）的缓释药物时（药物洗脱支架; DES）。然而，最近，在支架展开数月后抗凝治疗结束后，大量DES患者报告了晚期支架血栓形成。该项目提出，目前使用的支架支柱的物理形状创造了一个促进炎症和血栓形成的流动环境，流线型支架支柱几何形状将减少或消除流动扰动，预计血栓形成风险会降低。在将流线型设计引入动物模型之前，重要的是通过进行数值模拟来优化几何形状，并通过实验流体流动测量来证明它，同时通过使用血液和血管细胞的受控实验来证明生物学原理的证据。该项目测试了与支架功能相关的重要血流动力学假设，是动物模型临床前测试的重要探索性桥梁。成功实施有效的支架重新设计将对支架的使用和有效性产生重要影响。

DESCRIPTION (provided by applicant): Drug-eluting stents (DES) are deployed to physically reopen stenotic regions of coronary arteries to restore blood flow to the heart and to inhibit restenosis by release of anti-proliferative drugs over an extended period. However, significant incidences of localized delayed inflammation and late stent thrombosis (LST) leading to morbidities and deaths several months-to-years after deployment were reported in 2006. These alerted the FDA to reconsider the safety of DES and to issue a safety warning. Because DES inhibits restenosis, the stent struts remain at the arterial surface in indefinite contact with the flowing blood instead of being rapidly overgrown by the neointima. Although averaging only 1005m in height, the struts significantly change the local flow characteristics to create flow separation zones containing unsteady vortices in the regions adjacent to the stent strut. These vortices are characterized by significantly lower blood flow velocities than the bulk flow and prolonged particle residence time. We propose that the flow separation regions represent micro-reaction chambers where pro-coagulant and pro-inflammatory elements from the blood and vessel wall accumulate. Furthermore, re-endothelialization of the stented region is inhibited by low shear stress of the separation zones thereby contributing to a pro-pathological environment. Learning from numerical simulations of coronary blood flow and our extensive hemodynamic studies of arterial geometries where natural blood flow disturbances such as unsteady vortices induce pro-pathological vascular cell phenotypes, we hypothesize that the stent strut geometry leads to a local pro-thrombotic and pro-inflammatory environment. This R21 research grant proposes topographic solutions to mitigate or eliminate these consequences and tests them by experiment under controlled conditions in vitro, which is a necessary set of proof-of-principle exploratory studies that precede experiments in vivo. Guided by fundamental fluid dynamic principles, CFD numerical simulations identified a range of streamlined stent strut geometries that minimize or eliminate flow separation. Aim 1 will use Particle Image Velocimetry to characterize the flow field about different manufactured strut stent geometries in a cell culture flow chamber modeling coronary arterial flow and in a flow tube scaled to manageable quantities of whole blood. Aim 2 will test the effects of the respective strut designs on deposition of activated platelets and characteristics of thrombus growth in a chemical and substrate milieu conducive to thrombosis. Finally, Aim 3 will evaluate the effects of the redesigned stents on re-endothelialization and the expression of coagulation-related molecular phenotypes of endothelium. The proposal addresses the mechanisms of an important clinical problem by exploring the potential high utility of stent redesign and is built upon our extensive experience in hemodynamics, biomedical engineering and vascular cell and molecular pathology. The same principles of streamlined strut design are also applicable to BMS where thrombosis linked to the physical presence of the stent at the vessel surface occurs earlier, before a neointima develops. PUBLIC HEALTH RELEVANCE: Coronary artery stents are a common and effective treatment for angina and heart attacks particularly when the metal stent is coated with a slow-release drug that inhibits tissue response-driven reclosure (restenosis) of the artery (drug eluting stents; DES). Recently however, late stent thrombosis has been reported in a significant number of DES patients after anti-coagulant therapy has ended months after stent deployment. This project proposes that the physical shape of currently used stent struts creates a flow environment that promotes inflammation and thrombosis, and that a streamlined stent strut geometry will reduce or eliminate flow disturbances with a predicted decrease in thrombosis risk. Before taking the streamlined designs into an animal model, it is important to optimize the geometry by conducting numerical simulations and proving it with experimental fluid flow measurements while demonstrating proof of biological principles through controlled experiments using blood and vascular cells. The project tests an important hemodynamics hypothesis related to stent function and is an essential exploratory bridge to preclinical testing in an animal model. Successful implementation of effective stent redesign will have an important impact on the use and efficacy of stents.