Mitigation of stent-mediated pathology by streamlined geometry

描述（由申请人提供）：药物洗脱支架（DES）用于重新打开冠状动脉狭窄区域，以恢复心脏血液流动，并通过长时间释放抗增殖药物来抑制再狭窄。然而，2006年有报道称，局部迟发性炎症和晚期支架血栓形成（LST）的发生率很高，可导致支架置入数月至数年后的发病和死亡。这些警示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，支架支撑物保留在动脉表面，与流动的血液无限期接触，而不是被新生内膜迅速生长。支板虽然平均高度只有1005m，但显著改变了局部流动特性，在支架支板邻近区域形成了包含非定常涡的流动分离区。这些漩涡的特点是血流速度明显低于体流，颗粒停留时间延长。我们提出，流动分离区代表微反应室，促凝剂和促炎元素从血液和血管壁积累。此外，分离区的低剪切应力抑制了支架区域的再内皮化，从而促进了病理环境。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中学习，其中自然血流干扰如不稳定漩涡诱导病理血管细胞表型，我们假设支架支撑几何形状导致局部促血栓和促炎症环境。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，并通过体外受控条件下的实验对其进行测试，这是在体内实验之前必要的一组原理验证探索性研究。在流体动力学基本原理的指导下，CFD数值模拟确定了一系列最小化或消除流动分离的流线型支架支撑几何形状。目标1将使用粒子图像测速来表征不同制造支架几何形状的流场，在模拟冠状动脉血流的细胞培养流室和按比例缩放到可管理的全血量的流管中。目的2将测试在有利于血栓形成的化学和基质环境中，各自支撑设计对活化血小板沉积和血栓生长特征的影响。最后，Aim 3将评估重新设计的支架对内皮再内皮化和内皮凝固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一个重要的临床问题的机制，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之上。流线型支架设计的相同原则也适用于BMS，其中血栓形成与血管表面支架的物理存在有关，在新生内膜形成之前就发生了。公共卫生相关性：冠状动脉支架是治疗心绞痛和心脏病的一种常见且有效的方法，特别是当金属支架上涂有一种缓释药物，可以抑制组织反应驱动的动脉再狭窄（药物洗脱支架；DES）。然而，最近有报道称，大量DES患者在支架置放数月后抗凝治疗结束后出现晚期支架血栓形成。该项目提出，目前使用的支架支撑的物理形状创造了一个促进炎症和血栓形成的流动环境，流线型支架支撑几何形状将减少或消除流动干扰，从而降低血栓形成的风险。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和实验流体流动测量来优化几何形状，同时通过使用血液和血管细胞的对照实验来证明生物学原理。该项目测试了与支架功能相关的重要血流动力学假设，是动物模型临床前试验的重要探索性桥梁。有效支架重新设计的成功实施将对支架的使用和疗效产生重要影响。

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.